Position Statement on Fat Consumption and Cardiovascular Health – 2021

Maria Cristina de Oliveira Izar Ana Maria Lottenberg Viviane Zorzanelli Rocha Giraldez Raul Dias dos Santos Filho Roberta Marcondes Machado Adriana Bertolami Marcelo Heitor Vieira Assad José Francisco Kerr Saraiva André Arpad Faludi Annie Seixas Bello Moreira Bruno Geloneze Carlos Daniel Magnoni Carlos Scherr Cristiane Kovacs Amaral Daniel Branco de Araújo Dennys Esper Corrêa Cintra Edna Regina Nakandakare Francisco Antonio Helfenstein Fonseca Isabela Cardoso Pimentel Mota José Ernesto dos Santos Juliana Tieko Kato Lis Mie Masuzawa Beda Lis Proença Vieira Marcelo Chiara Bertolami Marcelo Macedo Rogero Maria Silvia Ferrari Lavrador Miyoko Nakasato Nagila Raquel Teixeira Damasceno Renato Jorge Alves Lara Roberta Soares Rosana Perim Costa Valéria Arruda Machado About the authors

Position Statement on Fat Consumption and Cardiovascular Health – 2021 The report below lists declarations of interest as reported to the SBC by the experts during the period of the development of these update, 2020. Expert Type of relationship with industry Adriana Bertolami Nothing to be declared Ana Maria Lottenberg FINANCIAL DECLARATION A - ECONOMICALLY RELEVANT PAYMENTS OF ANY KIND MADE TO (i) YOU, (ii) YOUR SPOUSE/PARTNER OR ANY OTHER PERSON LIVING WITH YOU, (iii) ANY LEGAL PERSON IN WHICH ANY OF THESE IS EITHER A DIRECT OR INDIRECT CONTROLLING OWNER, BUSINESS PARTNER, SHAREHOLDER OR PARTICIPANT; ANY PAYMENTS RECEIVED FOR LECTURES, LESSONS, TRAINING INSTRUCTION, COMPENSATION, FEES PAID FOR PARTICIPATION IN ADVISORY BOARDS, INVESTIGATIVE BOARDS OR OTHER COMMITTEES, ETC. FROM THE BRAZILIAN OR INTERNATIONAL PHARMACEUTICAL, ORTHOSIS, PROSTHESIS, EQUIPMENT AND IMPLANTS INDUSTRY: - PTC: medicines Andre Arpad Faludi Nothing to be declared Annie Seixas Bello Moreira Nothing to be declared Bruno Geloneze FINANCIAL DECLARATION A - ECONOMICALLY RELEVANT PAYMENTS OF ANY KIND MADE TO (i) YOU, (ii) YOUR SPOUSE/PARTNER OR ANY OTHER PERSON LIVING WITH YOU, (iii) ANY LEGAL PERSON IN WHICH ANY OF THESE IS EITHER A DIRECT OR INDIRECT CONTROLLING OWNER, BUSINESS PARTNER, SHAREHOLDER OR PARTICIPANT; ANY PAYMENTS RECEIVED FOR LECTURES, LESSONS, TRAINING INSTRUCTION, COMPENSATION, FEES PAID FOR PARTICIPATION IN ADVISORY BOARDS, INVESTIGATIVE BOARDS OR OTHER COMMITTEES, ETC. FROM THE BRAZILIAN OR INTERNATIONAL PHARMACEUTICAL, ORTHOSIS, PROSTHESIS, EQUIPMENT AND IMPLANTS INDUSTRY: - Novo Nordisk: diabetes - AstraZeneca: diabetes - MSD: diabetes OTHER RELATIONSHIPS FUNDING OF CONTINUING MEDICAL EDUCATION ACTIVITIES, INCLUDING TRAVEL, ACCOMMODATION AND REGISTRATION IN CONFERENCES AND COURSES, FROM THE BRAZILIAN OR INTERNATIONAL PHARMACEUTICAL, ORTHOSIS, PROSTHESIS, EQUIPMENT AND IMPLANTS INDUSTRY: - Novo Nordisk: diabetes Carlos Scherr OTHER RELATIONSHIPS FUNDING OF CONTINUING MEDICAL EDUCATION ACTIVITIES, INCLUDING TRAVEL, ACCOMMODATION AND REGISTRATION IN CONFERENCES AND COURSES, FROM THE BRAZILIAN OR INTERNATIONAL PHARMACEUTICAL, ORTHOSIS, PROSTHESIS, EQUIPMENT AND IMPLANTS INDUSTRY: - Bayer: thrombosis Cristiane Kovacs Amaral Nothing to be declared Daniel Branco de Araújo FINANCIAL DECLARATION A - ECONOMICALLY RELEVANT PAYMENTS OF ANY KIND MADE TO (i) YOU, (ii) YOUR SPOUSE/PARTNER OR ANY OTHER PERSON LIVING WITH YOU, (iii) ANY LEGAL PERSON IN WHICH ANY OF THESE IS EITHER A DIRECT OR INDIRECT CONTROLLING OWNER, BUSINESS PARTNER, SHAREHOLDER OR PARTICIPANT; ANY PAYMENTS RECEIVED FOR LECTURES, LESSONS, TRAINING INSTRUCTION, COMPENSATION, FEES PAID FOR PARTICIPATION IN ADVISORY BOARDS, INVESTIGATIVE BOARDS OR OTHER COMMITTEES, ETC. FROM THE BRAZILIAN OR INTERNATIONAL PHARMACEUTICAL, ORTHOSIS, PROSTHESIS, EQUIPMENT AND IMPLANTS INDUSTRY: - Novo Nordisk: diabetes - Sanofi: dislipidemia OTHER RELATIONSHIPS FUNDING OF CONTINUING MEDICAL EDUCATION ACTIVITIES, INCLUDING TRAVEL, ACCOMMODATION AND REGISTRATION IN CONFERENCES AND COURSES, FROM THE BRAZILIAN OR INTERNATIONAL PHARMACEUTICAL, ORTHOSIS, PROSTHESIS, EQUIPMENT AND IMPLANTS INDUSTRY: - Sanofi: dislipidemia Carlos Daniel Magnoni Nothing to be declared Dennys Esper Corrêa Cintra Nothing to be declared Edna Regina Nakandakare Nothing to be declared Francisco Antonio Helfenstein Fonseca FINANCIAL DECLARATION A - ECONOMICALLY RELEVANT PAYMENTS OF ANY KIND MADE TO (i) YOU, (ii) YOUR SPOUSE/PARTNER OR ANY OTHER PERSON LIVING WITH YOU, (iii) ANY LEGAL PERSON IN WHICH ANY OF THESE IS EITHER A DIRECT OR INDIRECT CONTROLLING OWNER, BUSINESS PARTNER, SHAREHOLDER OR PARTICIPANT; ANY PAYMENTS RECEIVED FOR LECTURES, LESSONS, TRAINING INSTRUCTION, COMPENSATION, FEES PAID FOR PARTICIPATION IN ADVISORY BOARDS, INVESTIGATIVE BOARDS OR OTHER COMMITTEES, ETC. FROM THE BRAZILIAN OR INTERNATIONAL PHARMACEUTICAL, ORTHOSIS, PROSTHESIS, EQUIPMENT AND IMPLANTS INDUSTRY: - Novo Nordisk: antidiabetic - Libbs: lipid-lowering - Ache: lipid-lowering C - PERSONAL RESEARCH FUNDING PAID BY THE BRAZILIAN OR INTERNATIONAL PHARMACEUTICAL, ORTHOSIS, PROSTHESIS, EQUIPMENT AND IMPLANTS INDUSTRY: - AstraZeneca: projeto de iniciativa do investigador, já concluído - Amgen: lipid-lowering - Biolab: vitamins OTHER RELATIONSHIPS FUNDING OF CONTINUING MEDICAL EDUCATION ACTIVITIES, INCLUDING TRAVEL, ACCOMMODATION AND REGISTRATION IN CONFERENCES AND COURSES, FROM THE BRAZILIAN OR INTERNATIONAL PHARMACEUTICAL, ORTHOSIS, PROSTHESIS, EQUIPMENT AND IMPLANTS INDUSTRY: - Bayer: anticoagulant - Sanofi: lipid-lowering - Amgen: lipid-lowering Isabela Cardoso Pimentel Mota Nothing to be declared Jose Ernesto dos Santos Nothing to be declared José Francisco Kerr Saraiva Nothing to be declared Juliana Tieko Kato Nothing to be declared Lis Mie Masuzawa Beda Nothing to be declared Lis Proença Vieira Nothing to be declared Marcelo Chiara Bertolami FINANCIAL DECLARATION A - ECONOMICALLY RELEVANT PAYMENTS OF ANY KIND MADE TO (i) YOU, (ii) YOUR SPOUSE/PARTNER OR ANY OTHER PERSON LIVING WITH YOU, (iii) ANY LEGAL PERSON IN WHICH ANY OF THESE IS EITHER A DIRECT OR INDIRECT CONTROLLING OWNER, BUSINESS PARTNER, SHAREHOLDER OR PARTICIPANT; ANY PAYMENTS RECEIVED FOR LECTURES, LESSONS, TRAINING INSTRUCTION, COMPENSATION, FEES PAID FOR PARTICIPATION IN ADVISORY BOARDS, INVESTIGATIVE BOARDS OR OTHER COMMITTEES, ETC. FROM THE BRAZILIAN OR INTERNATIONAL PHARMACEUTICAL, ORTHOSIS, PROSTHESIS, EQUIPMENT AND IMPLANTS INDUSTRY: - Abbott: dislipidemias - fenofibrato - Ache: dislipidemias - fenofibrato - Libbs: dislipidemias - fenofibrato - Merck: dislipidemias - fenofibrato - Novo Nordisk: dislipidemias - fenofibrato - Sanofi: dislipidemias - fenofibrato OTHER RELATIONSHIPS FUNDING OF CONTINUING MEDICAL EDUCATION ACTIVITIES, INCLUDING TRAVEL, ACCOMMODATION AND REGISTRATION IN CONFERENCES AND COURSES, FROM THE BRAZILIAN OR INTERNATIONAL PHARMACEUTICAL, ORTHOSIS, PROSTHESIS, EQUIPMENT AND IMPLANTS INDUSTRY: - Merck: dyslipidemia - statins - Novo Nordisk: dyslipidemia - statins - Sanofi: dyslipidemia - statins Marcelo Heitor Vieira Assad FINANCIAL DECLARATION A - ECONOMICALLY RELEVANT PAYMENTS OF ANY KIND MADE TO (i) YOU, (ii) YOUR SPOUSE/PARTNER OR ANY OTHER PERSON LIVING WITH YOU, (iii) ANY LEGAL PERSON IN WHICH ANY OF THESE IS EITHER A DIRECT OR INDIRECT CONTROLLING OWNER, BUSINESS PARTNER, SHAREHOLDER OR PARTICIPANT; ANY PAYMENTS RECEIVED FOR LECTURES, LESSONS, TRAINING INSTRUCTION, COMPENSATION, FEES PAID FOR PARTICIPATION IN ADVISORY BOARDS, INVESTIGATIVE BOARDS OR OTHER COMMITTEES, ETC. FROM THE BRAZILIAN OR INTERNATIONAL PHARMACEUTICAL, ORTHOSIS, PROSTHESIS, EQUIPMENT AND IMPLANTS INDUSTRY: - AstraZeneca: prevenção cardiovascular - Boeringher: diabetes/anticoagulação - Novo Nordisk: diabetes OTHER RELATIONSHIPS FUNDING OF CONTINUING MEDICAL EDUCATION ACTIVITIES, INCLUDING TRAVEL, ACCOMMODATION AND REGISTRATION IN CONFERENCES AND COURSES, FROM THE BRAZILIAN OR INTERNATIONAL PHARMACEUTICAL, ORTHOSIS, PROSTHESIS, EQUIPMENT AND IMPLANTS INDUSTRY: - Boeringher: diabetes - Novo Nordisk: diabetes Marcelo Macedo Rogero Nothing to be declared Maria Cristina de Oliveira Izar FINANCIAL DECLARATION A - ECONOMICALLY RELEVANT PAYMENTS OF ANY KIND MADE TO (i) YOU, (ii) YOUR SPOUSE/PARTNER OR ANY OTHER PERSON LIVING WITH YOU, (iii) ANY LEGAL PERSON IN WHICH ANY OF THESE IS EITHER A DIRECT OR INDIRECT CONTROLLING OWNER, BUSINESS PARTNER, SHAREHOLDER OR PARTICIPANT; ANY PAYMENTS RECEIVED FOR LECTURES, LESSONS, TRAINING INSTRUCTION, COMPENSATION, FEES PAID FOR PARTICIPATION IN ADVISORY BOARDS, INVESTIGATIVE BOARDS OR OTHER COMMITTEES, ETC. FROM THE BRAZILIAN OR INTERNATIONAL PHARMACEUTICAL, ORTHOSIS, PROSTHESIS, EQUIPMENT AND IMPLANTS INDUSTRY: - Amgen: dyslipidemia - Ache: dyslipidemia - Novartis: dyslipidemia - PTCbio: dyslipidemia B - RESEARCH FUNDING UNDER YOUR DIRECT/PERSONAL RESPONSIBILITY (DIRECTED TO THE DEPARTMENT OR INSTITUTION) FROM THE BRAZILIAN OR INTERNATIONAL PHARMACEUTICAL, ORTHOSIS, PROSTHESIS, EQUIPMENT AND IMPLANTS INDUSTRY: - Amgen: dyslipidemia - PTCbio: dyslipidemia - Novartis: dyslipidemia OTHER RELATIONSHIPS FUNDING OF CONTINUING MEDICAL EDUCATION ACTIVITIES, INCLUDING TRAVEL, ACCOMMODATION AND REGISTRATION IN CONFERENCES AND COURSES, FROM THE BRAZILIAN OR INTERNATIONAL PHARMACEUTICAL, ORTHOSIS, PROSTHESIS, EQUIPMENT AND IMPLANTS INDUSTRY: - Amgen: dyslipidemia - Novo Nordisk: GLP-1RA - PTCbio: dyslipidemia Maria Silvia Ferrari Lavrador Nothing to be declared Miyoko Nakasato Nothing to be declared Nagila Raquel Teixeira Damasceno Nothing to be declared Raul Dias dos Santos Filho FINANCIAL DECLARATION A - ECONOMICALLY RELEVANT PAYMENTS OF ANY KIND MADE TO (i) YOU, (ii) YOUR SPOUSE/PARTNER OR ANY OTHER PERSON LIVING WITH YOU, (iii) ANY LEGAL PERSON IN WHICH ANY OF THESE IS EITHER A DIRECT OR INDIRECT CONTROLLING OWNER, BUSINESS PARTNER, SHAREHOLDER OR PARTICIPANT; ANY PAYMENTS RECEIVED FOR LECTURES, LESSONS, TRAINING INSTRUCTION, COMPENSATION, FEES PAID FOR PARTICIPATION IN ADVISORY BOARDS, INVESTIGATIVE BOARDS OR OTHER COMMITTEES, ETC. FROM THE BRAZILIAN OR INTERNATIONAL PHARMACEUTICAL, ORTHOSIS, PROSTHESIS, EQUIPMENT AND IMPLANTS INDUSTRY: Abbott: cardiology Ache: cardiology AstraZeneca: cardiology Amgen: cardiology Novo Nordisk: cardiology Novartis: cardiology PTC Therapeutics: cardiology Sanofi/Regeneron: cardiology B - RESEARCH FUNDING UNDER YOUR DIRECT/PERSONAL RESPONSIBILITY (DIRECTED TO THE DEPARTMENT OR INSTITUTION) FROM THE BRAZILIAN OR INTERNATIONAL PHARMACEUTICAL, ORTHOSIS, PROSTHESIS, EQUIPMENT AND IMPLANTS INDUSTRY: Amgen: cardiology Esperion: cardiology Kowa: cardiology Sanofi/Regeneron: cardiology Renato Jorge Alves Nothing to be declared Roberta Marcondes Machado Nothing to be declared Roberta Soares Lara Nothing to be declared Rosana Perim Costa Nothing to be declared Valéria Arruda Machado Nothing to be declared Viviane Zorzanelli Rocha FINANCIAL DECLARATION A - ECONOMICALLY RELEVANT PAYMENTS OF ANY KIND MADE TO (i) YOU, (ii) YOUR SPOUSE/PARTNER OR ANY OTHER PERSON LIVING WITH YOU, (iii) ANY LEGAL PERSON IN WHICH ANY OF THESE IS EITHER A DIRECT OR INDIRECT CONTROLLING OWNER, BUSINESS PARTNER, SHAREHOLDER OR PARTICIPANT; ANY PAYMENTS RECEIVED FOR LECTURES, LESSONS, TRAINING INSTRUCTION, COMPENSATION, FEES PAID FOR PARTICIPATION IN ADVISORY BOARDS, INVESTIGATIVE BOARDS OR OTHER COMMITTEES, ETC. FROM THE BRAZILIAN OR INTERNATIONAL PHARMACEUTICAL, ORTHOSIS, PROSTHESIS, EQUIPMENT AND IMPLANTS INDUSTRY: - Amgen: evolocumabe - Novo Nordisk: diabetes - AstraZeneca: dapagliflozina OTHER RELATIONSHIPS FUNDING OF CONTINUING MEDICAL EDUCATION ACTIVITIES, INCLUDING TRAVEL, ACCOMMODATION AND REGISTRATION IN CONFERENCES AND COURSES, FROM THE BRAZILIAN OR INTERNATIONAL PHARMACEUTICAL, ORTHOSIS, PROSTHESIS, EQUIPMENT AND IMPLANTS INDUSTRY: - Amgen: evolocumabe

List of Abbreviations

ABCA1 - ATP binding cassette transporters A1

ABCG1 - ATP binding cassette transporters G1

ACC - American College of Cardiology

Acetyl-CoA - acetyl-coenzyme A

AHA - American Heart Association

Akt - protein kinase B

ALA - alpha-linolenic acid

AMI - acute myocardial infarction

AMPK – AMP-activated protein kinase

APoA-I - apolipoprotein AI

APoB - apolipoprotein B

AST - aspartate transaminase

BMI – body mass index

CAD - coronary artery disease

CE - cholesteryl ester

CETP - cholesteryl ester transfer protein

CHS - Cardiovascular Health Study

CRP - C-reactive protein

CVD - cardiovascular disease

DASH - Dietary Approaches to Stop Hypertension

DHA - docosahexaenoic acid

DIVAS - Dietary Intervention and VAScular function

DPA - docosapentaenoic acid

DRI - Dietary Reference Intakes

EAS - European Atherosclerosis Society

eNOS - endothelial nitric oxide synthase

EPA - eicosapentaenoic acid

EPIC - European Prospective Investigation into Cancer and Nutrition

ER - endoplasmic reticulum

ESC - European Society of Cardiology

FCS - familial chylomicronemia syndrome

FFA - free fatty acid

HbA1c - glycated hemoglobin

HF - heart failure

HMG-CoA - 3-hydroxy-3-methylglutaryl coenzyme A

HOMA-IR - homeostasis model assessment of insulin resistance

HPFS - Health Professionals Follow-up Study

ICAM - intercellular adhesion molecule

IKK - IκB kinase

IL - interleukin

iNOS - inducible nitric oxide synthase

IRS-1 - insulin receptor substrate-1

JACC - Japan Collaborative Cohort Study for Evaluation of Cancer Risk

JNK - c-Jun N-terminal kinase

LOX-1 - oxidized LDL receptor-1

LPL - lipoprotein lipase

LPS - lipopolysaccharide

MCP - monocyte chemoattractant protein

MRI - magnetic resonance imaging

MUFA - monounsaturated fatty acid

NAFLD - nonalcoholic fatty liver disease

NASH - nonalcoholic steatohepatitis

NCD - noncommunicable disease

NF-kB - nuclear factor kappa B

NHANES - National Health and Nutrition Examination Survey

NHS - Nurses’ Health Study

NO - nitric oxide

NYHA - New York Heart Association

ORIGIN - Outcome Reduction with an Initial Glargine Intervention

PGC - peroxisome proliferator-activated receptor gamma coactivator

PGE2 - prostaglandin E2

PKC – protein kinase C

PPARγ-2 - peroxisome proliferator-activated receptor gamma

PREDIMED - Prevención con Dieta Mediterránea /Prevention with Mediterranean Diet

PUFA - polyunsaturated fatty acid

PURE - Prospective Urban Rural Epidemiology

ROS - reactive oxygen species

SFA – saturated fatty acid

SBC - Sociedade Brasileira de Cardiologia /Brazilian Society of Cardiology

SCD1 - stearoyl-CoA desaturase-1

SCFA - short-chain fatty acid

SMC - smooth muscle cell

SREBP - sterol regulatory element-binding protein

T2D - type 2 diabetes

TC - total cholesterol

TG - triglyceride

TLR - toll-like receptor

TMA - trimethylamine

TMAO - trimethylamine N-oxide

TNF - tumor necrosis factor

UFA - unsaturated fatty acid

VCAM - vascular cell adhesion molecule

WHI - Women’s Health Initiative

WHO - World Health Organization

ω3 - omega-3

ω6 - omega-6

ω9 - omega-9

Definition of Grades of Recommendation and Levels of Evidence

Classes (grades) of recommendation:

Class I: conditions for which there is conclusive evidence, or, in the absence of conclusive evidence, there is general agreement that a given procedure is safe and useful/effective.

Class II: conditions for which there is conflicting evidence and/or a divergence of opinion about the safety and usefulness/efficacy of a procedure.

Class IIA: weight of evidence/opinion is in favor of the procedure; the majority agrees.

Class IIB: the safety and usefulness/efficacy are less well established, with no prevailing opinions in favor of the procedure.

Class III: conditions for which there is evidence and/or general agreement that the procedure is not useful/effective and in some cases may be harmful.

Levels of evidence:

Level A: data were derived from multiple randomized clinical trials that involved large numbers of patients with similar outcomes and/or robust meta-analyses of randomized clinical trials.

Level B: data were derived from less robust meta-analyses, a single randomized clinical trial, or non-randomized (observational) studies.

Level C: data were derived from consensus of expert opinion.

Cover Letter

Nutrition plays a key role in the genesis of noncommunicable diseases, which are currently considered one of the most important public health problems worldwide. The quality and quantity of food, in particular dietary sources of fats, can influence both the pathogenesis and prevention of cardiovascular diseases (CVDs). Experts all over the world have developed evidence-based guidelines on fat consumption and suggested an adequate amount of dietary fat, as well as limited consumption of saturated and trans fats. Priority has been given to assessing and proposing healthier eating patterns instead of valuing individual foods, with a much more rational approach to cardiovascular prevention by ensuring an adequate energy intake with the dietary inclusion of grains, fruits and vegetables, restriction of refined carbohydrates and ultra-processed foods, and intake of healthier fats rather than saturated and trans fats.

This position statement aims to guide health professionals in understanding the effects of different fatty acids and to propose appropriate dietary measures targeted at CVD prevention and control.

The Department of Atherosclerosis of the Brazilian Society of Cardiology brought together the country’s leading experts to prepare this document in a clear and objective manner in order to provide the best information available to improve clinical practice in our country for the prevention and treatment of CVD.

Yours sincerely,

Prof. Maria Cristina de Oliveira Izar, PhD

Content

1. Introduction 169

2. Fatty Acid Classification and Sources 170

2.1. Monounsaturated Fatty Acids 170

2.2. Polyunsaturated Fatty Acids 171

2.3. Saturated Fatty Acids 171

2.4. Trans Fats 171

3. Plasma Concentration of Total Cholesterol and Lipoproteins 171

4. Plasma Concentration of Triglycerides 172

5. Cardiovascular and Coronary Heart Disease 173

5.1. Saturated Fatty Acids 173

5.2. Replacement of Saturated with Unsaturated Fatty Acids 174

5.3. Replacement of Saturated Fatty Acids with Carbohydrates 174

5.4. Polyunsaturated Fatty Acids (Omega-6) 174

5.5. Polyunsaturated Fatty Acids (Marine Omega-3) 175

5.5.1. Effects on Peripheral Vascular Disease 176

5.5.2. Effects on Cardiac Arrhythmia and Sudden Cardiac Death 176

5.5.3. Effects on Heart Failure 176

5.6. Polyunsaturated Fatty Acids (Vegetable Omega-3) 176

5.7. Trans Fats 177

6. Endothelial Dysfunction 177

6.1. Blood Pressure 178

6.2. Stroke 178

7. Inflammation 179

8. Insulin Resistance and Diabetes 180

9. Fatty Liver Disease 181

9.1. Hepatic Steatosis 181

9.2. Saturated Fatty Acids and Nonalcoholic Steatohepatitis 182

9.3. Unsaturated Fatty Acids and Nonalcoholic Steatohepatitis 182

9.4. Trans Fatty Acids and Nonalcoholic Steatohepatitis 183

10. Lipid Metabolism in Adipose Tissue 183

10.1. Saturated Fatty Acids and Adipose Tissue Metabolism 184

10.2. Unsaturated Fatty Acids and Adipose Tissue Metabolism 184

11. Food 185

11.1. Coconut Oil 185

11.2. Palm Oil 185

11.3. Chocolate 186

11.4. Butter 186

11.5. Dairy 186

11.6. Meat 186

12. Gut Microbiota 187

12.1. Dietary Patterns and Gut Microbiota 187

12.2. Importance of Dietary Pattern in Short-chain Fatty Acid Synthesis 187

13. Dietary Cholesterol 188

13.1. Plasma Concentration of Lipids and Lipoproteins 188

13.2. Risk of Developing Type 2 Diabetes 188

13.3. Risk of Cardiovascular Diseases in Type 2 Diabetes 188

13.4. Impact on Cardiovascular Diseases 189

14. Egg 189

14.1. Trimethylamine N-oxide in Cardiovascular Diseases 189

14.2. Hepatic Steatosis 190

15. Interesterified Fats 190

15.1. Studies in Animals 190

15.2. Studies in Humans 191

16. Medium-chain Triglycerides 191

17. Familial Chylomicronemia Syndrome 191

18. Practical Aspects of Nutritional Intervention 192

19. Labeling and Trans Fatty Acids 192

20. Final Considerations 192

21. Nutritional Amounts of Fatty Acids and Cholesterol in Foods 193

22. Grade of Recommendations and Level of Evidence: Fatty Acids and Cardiovascular Disease 196

References 196

1. Introduction

The relevance of diet in the genesis of noncommunicable diseases (NCDs) is well documented in the literature.11. Global Burden Disease. (GBD) 2017 Diet Collaborators. Health effects of dietary risks in 195 countries,1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2019;393(10184):1958-1972.This set of diseases is currently considered one of the most important public health problems and accounts for approximately 71% of mortality worldwide.22. World Health Organization (WHO). Global Health Observatory. [Cited in 2019 Dec 12]. Available from: https://www.who.int/gho/ncd/mortality_morbidity/en/
https://www.who.int/gho/ncd/mortality_mo...
In Brazil, in 2016, NCDs were associated with 74% of total deaths, especially cardiovascular diseases (CVDs).33. Brasil. Ministério da Saúde. Vigitel Brasil 2018: vigilância de fatores de risco e proteção para doenças crônicas por inquérito telefônico: estimativas sobre frequência e distribuição sócio demográfica de fatores de risco e proteção para doenças crônicas nas capitais dos 26 estados brasileiros e no Distrito Federal em 2018. Brasília; 2019.The quality and quantity of food, in particular dietary sources of fats, can influence both the pathogenesis and prevention of CVD.

Guidelines and statements on fat consumption have been developed for over 50 years, first published by the American Heart Association (AHA).44. Page IH, Stareb FJ, Corcoran AC et al. Atherosclerosis and the fat content of the diet. J Am Med Assoc. 1957; 164(18):2048-51.In the last decades, government agencies and international medical societies, such as the World Health Organization (WHO), United States Government, Institute of Medicine, and European Food Safety Authority, among others, have been engaged in the development of scientific reports based on high-quality evidence.55. The Facts on Fats. 50 years of American Heart Association - Dietary Fats Recomendations. American Heart Association; American Stroke Association. https://www.heart.org/-/media/files/healthy-living/company collaboration/inap/fats-white-paper-ucm_475005.pdf.
https://www.heart.org/-/media/files/heal...
In Brazil, the first guideline on fat consumption was published in 2013 by the Brazilian Society of Cardiology (SBC).66. Santos RD, Gagliardi AC, Xavier HT et al; Sociedade Brasileira de Cardiologia. First guidelines on fat consumption and cardiovascular health. Arq Bras Cardiol. 2013;100(1 Suppl 3):1-40.

The first studies, published in the 1950s, showed that increased fat intake was significantly associated with an increased prevalence of atherosclerosis.44. Page IH, Stareb FJ, Corcoran AC et al. Atherosclerosis and the fat content of the diet. J Am Med Assoc. 1957; 164(18):2048-51.Preliminary studies were based on the analysis of population-based data obtained from dietary surveys, which evaluated the effects of the amount and types of saturated (SFA) and unsaturated (UFA) fatty acids on mortality and CVD. Therefore, the first recommendation regarding fat consumption established a maximum limit of 30% of total energy intake from fat and recommended a reduction in the intake of SFAs.44. Page IH, Stareb FJ, Corcoran AC et al. Atherosclerosis and the fat content of the diet. J Am Med Assoc. 1957; 164(18):2048-51.Subsequent guidelines published by the AHA55. The Facts on Fats. 50 years of American Heart Association - Dietary Fats Recomendations. American Heart Association; American Stroke Association. https://www.heart.org/-/media/files/healthy-living/company collaboration/inap/fats-white-paper-ucm_475005.pdf.
https://www.heart.org/-/media/files/heal...
and the 2015-2020 Dietary Guidelines for Americans77. U.S. Department of Health and Human Services and U.S. Department of Agriculture. 2015 – 2020 Dietary Guidelines for Americans. 8th ed Dec, 2015.followed the same line of recommendation for CVD prevention, establishing a maximum limit of 35% of energy from fat, varying according to the lipid profile of each individual. In addition, recommendations included a maximum SFA intake of 10% of energy, promotion of UFA intake, and exclusion of trans fatty acids from the diet.

Thus, the AHA recommendation of a low-fat diet has, in fact, the aim to suggest an adequate amount of fat intake. This recommendation was based on the very high intake of fat by the American population (36-46% of energy), which was associated with increased cardiovascular risk. In addition, only for hypercholesterolemic individuals, the American College of Cardiology (ACC) and AHA88. Eckel RH, Jakicic JM, Ard JD et al; American College of Cardiology/American Heart Association Task Force on Practice Guidelines. 2013 AHA/ACC guideline on lifestyle management to reduce cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014; 129(25 Suppl 2):S76-99. , 99. Grundy SM, Stone NJ, Bailey AL et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2019; 139(25):e1082-143 recommend a limit of 5 to 6% of calories from SFAs. Likewise, the 2019 European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) guidelines for the management of dyslipidemias: lipid modification to reduce cardiovascular risk1010. Mach F, Baigent C, Catapano AL et al; ESC Scientific Document Group. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J. 2020; 41(1):111-88.recommend limiting the intake of SFAs (<7% of energy) and total fat (<35% of energy).

Controversial results are common in the field of nutrition research, due to inconsistency in protocols regarding study period, study population, sample size, and type of nutrient used in the comparison group.1010. Mach F, Baigent C, Catapano AL et al; ESC Scientific Document Group. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J. 2020; 41(1):111-88.The replacement of calories from SFAs with polyunsaturated (PUFA) and monounsaturated (MUFA) fatty acids reduces cardiovascular risk,1111. Mensink RP. Effects of saturated fatty acids on serum lipids and lipoproteins: a systematic review and regression analysis. Geneva, Switzerland: World Health Organization; 2016.whereas the replacement of SFAs with refined carbohydrates, such as sugar, elicits the opposite effect.1212. Siri-Tarino PW, Sun Q, Hu FB et al. Saturated fat, carbohydrate, and cardiovascular disease. Am J Clin Nutr. 2010;91(3):502-9.In addition, SFAs can be found in a wide variety of foods, with different structure and composition, such as meat, milk, oils, and processed foods. The fact that SFAs are present in fat emulsions, such as milk, and in solid matrices of palm oil with sugar, such as store-bought cookies, induce different effects on plasma lipids.1313. Astrup A, Bertram HC, Bonjour JP et al. WHO draft guidelines on dietary saturated and trans fatty acids: time for a new approach? BMJ. 2019 Jul; 366:l4137

Another important factor that can interfere in the analysis of the role of fatty acids is the dietary pattern in which they are consumed. From a cardiovascular point of view, SFAs can be associated with deleterious effects when consumed in a context of a diet high in sugar and low in fiber, whereas their negative impact may be attenuated in a context of healthy eating patterns.1414. Forouhi NG, Koulman A, Sharp SJ et al. Differences in the prospective association between individual plasma phospholipid saturated fatty acids and incident type 2 diabetes: the EPIC-InterAct case-cohort study. Lancet Diabetes Endocrinol. 2014; 2(10):810-8.

Although, in general, SFAs are associated with increased cardiovascular risk, it is important to note that not all SFAs increase plasma cholesterol levels and cardiovascular risk.1111. Mensink RP. Effects of saturated fatty acids on serum lipids and lipoproteins: a systematic review and regression analysis. Geneva, Switzerland: World Health Organization; 2016.In addition, several studies have shown that increased SFA intake can induce an increase in HDLc.1111. Mensink RP. Effects of saturated fatty acids on serum lipids and lipoproteins: a systematic review and regression analysis. Geneva, Switzerland: World Health Organization; 2016.However, this information should be interpreted with caution, because these HDL particles are enriched with pro-inflammatory proteins, which may reduce their functionality and affect some stage of reverse cholesterol transport.1515. O’Reilly M, Dillon E, Guo W et al. High-density lipoprotein proteomic composition, and not efflux capacity, reflects differential modulation of reverse cholesterol transport by saturated and monounsaturated fat diets. Circulation. 2016; 133(19):1838-50.

International guidelines point out the importance of following healthy eating patterns, such as a Mediterranean diet1616. Estruch R, Ros E, Salas-Salvadó J et al. Primary prevention of cardiovascular disease with a Mediterranean diet. N Engl J Med. 2013; 368(14):1279-90

17. Estruch R, Ros E, Salas-Salvadó J et al. Primary prevention of cardiovascular disease with a Mediterranean diet supplemented with extra-virgin olive oil or nuts. N Engl J Med. 2018; 378(25):e34.
- 1818. Estruch R, Ros E, Salas-Salvado J et al. Retraction and republication: primary prevention of cardiovascular disease with a Mediterranean diet. N Engl J Med 2018; 378(25):2441-2. and the Dietary Approaches to Stop Hypertension (DASH) diet.1919. Moore TJ, Vollmer WM, Appel LJ et al. Effect of dietary patterns on ambulatory blood pressure: results from the Dietary Approaches to Stop Hypertension (DASH) Trial. DASH Collaborative Research Group. Hypertension. 1999; 34(3):472-77.The Dietary Guidelines for the Brazilian Population2020. Brasil. Ministério da Saúde. Secretaria de Atenção à Saúde. Departamento de Atenção Básica. Guia alimentar para a população brasileira / Ministério da Saúde, Secretaria de Atenção à Saúde, Departamento de Atenção Básica. 2. ed., 1. reimpr. Brasília: 2014. pp. 156.also highlight the importance of following healthy eating patterns and emphasize that the study of isolated nutrients does not fully clarify the influence of diet on health. These guidelines also explain that benefits should be attributed less to an individual food and more to the combination of foods that characterize the dietary pattern.

As a common point, all these guidelines emphasize the importance of an adequate energy intake, inclusion of grains, fruits, and vegetables in the diet, and reduction of refined carbohydrates, especially sugars. Regarding fat intake, priority should be given to the consumption of MUFAs and PUFAs, with limited intake of SFAs, which is consistent with the AHA guidelines99. Grundy SM, Stone NJ, Bailey AL et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2019; 139(25):e1082-143on the recommended healthy profile of fat intake.

According to recent data from the National Health and Nutrition Examination Survey (NHANES) study, there has been a reduction in the intake of refined carbohydrates and SFAs by the American population. Nevertheless, this population still exceeds the recommended amount of these nutrients.2121. Shan Z, Rehm CD, Rogers G et al. Trends in Dietary Carbohydrate, Protein, and Fat Intake and Diet Quality Among US Adults, 1999-2016. JAMA. 2019; 322(12):1178-87.

In Brazil, no study has provided sufficient data for a detailed over-time analysis of the percentage consumption of fats. However, important results from the 2019 Brazilian Household Budget Survey (POF/IBGE),2222. Pesquisa de orçamentos familiares 2017-2018: primeiros resultados/IBGE, Coordenação de Trabalho e Rendimento. Rio de Janeiro: IBGE, 2019. pp. 69.which compared the period from 2017-2018 to 2002-2003, showed a significant decrease in household expenses with oils and fats. In addition, this survey showed a reduction in the intake of legumes (grains). The survey also showed that almost one-third of the population eats out, which increases the likelihood of eating in snack bars, where people often choose foods of low nutritional quality, that is, with a low content of fibers and vitamins and a high concentration of fats and refined carbohydrates. Although there was a small increase in household expenses with fruits, data from the 2018 Brazilian Telephone Survey for Surveillance of Risk and Protective Factors for Chronic Diseases (VIGITEL) show that only 24.4% of the population consumes fruits and vegetables within the amounts recommended by the Brazilian Ministry of Health33. Brasil. Ministério da Saúde. Vigitel Brasil 2018: vigilância de fatores de risco e proteção para doenças crônicas por inquérito telefônico: estimativas sobre frequência e distribuição sócio demográfica de fatores de risco e proteção para doenças crônicas nas capitais dos 26 estados brasileiros e no Distrito Federal em 2018. Brasília; 2019.and that 32% of the population eats high-fat meat daily. Moreover, ultra-processed foods that have low nutritional value, such as sandwich cookies, are those that most contribute to the consumption of SFAs and sugar.2222. Pesquisa de orçamentos familiares 2017-2018: primeiros resultados/IBGE, Coordenação de Trabalho e Rendimento. Rio de Janeiro: IBGE, 2019. pp. 69.

Brazil was one of the 195 countries included in the Global Burden of Disease Study 2017,11. Global Burden Disease. (GBD) 2017 Diet Collaborators. Health effects of dietary risks in 195 countries,1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2019;393(10184):1958-1972.whose main objective was to evaluate the impact of diet on NCD morbidity and mortality. The main causes of cardiovascular mortality attributable to diet included high intakes of sodium and trans fats and low intakes of fruits, vegetables, whole grains, and foods that are sources of PUFAs. The study also showed that, in Brazil, the main dietary risk factor associated with cardiovascular mortality and morbidity was low intake of grains, which, in our population, are mainly represented by beans. In fact, data collected by both Brazilian surveys, VIGITEL and POF, emphasize that there was a reduction in the consumption of beans, which, in addition to being part of the Brazilian food culture, are part of a healthy dietary pattern due to their low fat content and significant amount of fiber.

Despite the deleterious impact of trans fats on cardiovascular risk, a recent study conducted in Brazil revealed that one-fifth of packaged foods are still prepared with this fatty acid.2323. Ricardo CZ, Peroseni IM, Mais LA et al. Trans Fat Labeling Information on Brazilian Packaged Foods. Nutrients. 2019; 11(9). pii: E2130.In addition, other commonly consumed snack foods, such as fried or baked snacks, puff pastry, and pies, among others, are often prepared with trans fats. In this respect, the diet currently consumed by some Brazilians contrasts with current international recommendations on healthy eating.

The present position statement developed by SBC aims to describe recent advances regarding the effects of different fatty acids, ranging from their influence on the gut microbiota, liver lipid metabolism, and adipose tissue to the main aspects related to CVD risk and control.

2. Fatty Acid Classification and Sources

2.1. Monounsaturated Fatty Acids

MUFAs are characterized by the presence of a single double bond in the carbon chain. Oleic acid (omega-9) is the most abundant MUFA in nature, accounting for 90% of all MUFAs,2424. Kris-Etherton PM. AHA Science Advisory. Monounsaturated fatty acids and risk of cardiovascular disease. American Heart Association. Nutrition Committee. Circulation. 1999; 100(11):1253-8.with olive and canola oils as the main oil sources. MUFAs also play a prominent role in the composition of fatty acids in several nuts, such as macadamia nuts (59%), hazelnuts (46%), peanuts (41%), almonds (31%), cashews (27%), and pistachios (24%).2525. Universidade Estadual de Campinas – UNICAMP. Tabela brasileira de composição de alimentos – TACO. 4. ed. rev. e ampl. Campinas: UNICAMP/NEPA, 2011. pp. 161. Disponível em: http://www.unicamp.br/nepa/taco/tabela.
http://www.unicamp.br/nepa/taco/tabela...
Another oil rich in MUFAs is high oleic acid, which has been used in some countries and can be prepared from sunflower, canola, or soybean oils.2626. Tarrago-Trani MT, Phillips KM, Lemar LE et al. New and existing oils and fats used in products with reduced trans-fatty acids content. J Am Diet Assoc. 2006; 106(6):867-80. , 2727. Krumreich FD, Borges CD, Mendonça CRB et al. Bioactive compounds and quality parameters of avocado oil obtained by different processes. Food Chem. 2018 Aug; 257:376-81. With due attention to the high SFA content, meat products are also considered important sources of MUFAs, accounting in some cases for 40 to 50% of the composition of foods such as beef, chicken,2828. Almeida JC, Perassolo MS, Camargo JL et al. Fatty acid composition and cholesterol content of beef and chicken meat in Southern Brazil. Rev Bras Cienc Farm. 2006; 42(1):109-17.and pork.2929. Alfaia CM, Lopes PA, Madeira MS et al. Current feeding strategies to improve pork intramuscular fat content and its nutritional quality. Adv Food Nutr Res. 2019 Apr; 89:53-94.

2.2. Polyunsaturated Fatty Acids

PUFAs are part of a broad group of fats with two or more double bonds in the carbon chain. This characteristic confers widely different biological functions and, therefore, their impact on cardiovascular health is also distinct depending on the type of PUFA consumed. They are part of the omega-6 (ω6) or omega-3 (ω3) series depending on the position of the first double bond counted from the methyl end of the carbon chain. The ω6 fatty acids are classified as linoleic acid (18:2), whose main sources are oils (sunflower, corn, and soybean), walnuts, and Brazil nuts, and arachidonic acid (20:4), obtained from endogenous conversion of linoleic acid. The main ω3 fatty acids are alpha-linolenic acid (ALA [C18:3]) of plant origin, whose main sources are soybean, canola, flaxseed, and chia seeds,3030. Lee JH, O’Keefe JH, Lavie CJ et al. Omega-3 fatty acids: Cardiovascular benefits, sources and sustainability. Nat Rev Cardiol. 2009;6(12):753-58. , 3131. Bodkowski R, Czyz K, Kupczynski R et al. Lipid complex effect on fatty acid profile and chemical composition of cow milk and cheese. J Dairy Sci. 2016; 99(1):57–67. and eicosapentaenoic acid (EPA [C20:5]) and docosahexaenoic acid (DHA [C22:6]), found in fish and cold-water crustaceans from the Pacific and Artic oceans. Linoleic and linolenic fatty acids are considered essential for humans, and must be obtained from food. However, according to the Dietary Reference Intakes (DRI), supplementation is not necessary since a moderate intake of soybean or canola oil (about 15 mL/day) ensures an adequate consumption.3232. Trumbo P, Schlicker S, Yates AA et al. Food and Nutrition Board of the Institute of Medicine, The National Academies. Dietary reference intakes for energy, carbohydrate, fiber, fat, fatty acids, cholesterol, protein and amino acids. J Am Diet Assoc. 2002; 102(11):1621-30.EPA and DHA, on the other hand, can be produced endogenously by the enzymatic action of ALA desaturases and elongases, but this conversion is limited and affected by physiological and external factors.3333. Burdge GC, Wootton SA. Conversion of alpha-linolenic acid to eicosapentaenoic, docosapentaenoic and docosahexaenoic acids in young women. Br J Nutr. 2002; 88(4):411-20.

34. Harper CR, Edwards MJ, DeFilippis AP et al. Flaxseed oil increases the plasma concentrations of cardioprotective (n-3) fatty acids in humans. J Nutr. 2006;136(1):83-7.
- 3535. Baker EJ, Miles EA, Burdge GC et al. Metabolism and functional effects of plant-derived omega-3 fatty acids in humans. Prog Lipid Res. 2016 Oct; 64:30-56. Another source of EPA and DHA is krill oil, a shrimp-like crustacean found in the South Seas. Krill oil is a unique source of EPA and DHA, since most ω3 fatty acids are found in phospholipids, with greater bioavailability of krill ω3 compared to marine ω3.3636. Berge K, Musa-Veloso K, Harwood M et al. Krill oil supplementation lowers triglycerides without increasing low-density lipoprotein cholesterol in adults with borderline high or high triglyceride levels. Nutr Res. 2014;34(2):126-33.

2.3. Saturated Fatty Acids

SFAs have a simple molecular structure and are characterized by the absence of double bonds in the straight carbon chain. They are classified as short-chain (acetic acid [C2:0], propionic acid [C3:0], and butyrate [C4:0]), medium-chain (caproic [C6:0], caprylic [C8:0], and capric [C10:0] acids), and long-chain (lauric [C12:0], myristic [C14:0], palmitic [C16:0], and stearic [C18:0] acids).3737. Tvrzicka E, Kremmyda LS, Stankova B et al. Fatty acids as biocompounds: their role in human metabolism, health and disease--a review. Part 1: classification, dietary sources and biological functions. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2011; 155(22):117-30.In addition, they are also classified according to the melting point, a key feature to determine the absorption mechanism. Short- and medium-chain fatty acids (C2-C10), which have a low melting point, are absorbed via the portal system, whereas long-chain fatty acids (C14-C18) are absorbed via the lymphatic system by chylomicrons. Lauric acid is absorbed mostly by chylomicrons, but also via the portal system.3838. McDonald GB, Saunders DR, Weidman M et al. Portal venous transport of long-chain fatty acids absorbed from rat intestine. Am J Physiol. 1980; 239(3):G141-50.

This structural difference allows SFAs to have different biological and metabolic actions,3939. Rioux V, Legrand P. Saturated fatty acids: simple molecular structures with complex cellular functions. Curr Opin Clin Nutr Metab Care 2007; 10(6):752-8.acting as signaling agents to modulate the protein-protein and protein-plasma membrane interactions through processes known as myristoylation and protein palmitoylation.4040. Mitchell DA, Vasudevan A, Linder ME et al. Protein palmitoylation by a family of DHHC protein S-acyltransferases. J Lipid Res. 2006; 47(6):1118-27.

SFAs can be synthesized endogenously in most cells from acetyl-coenzyme A (acetyl-CoA) derived from the metabolism of carbohydrates, amino acids, and fats.4141. Calder PC. Functional roles of fatty acids and their effects on human health. JPEN J Parenter Enteral Nutr. 2015; 39(1 Supp):18S-32S.The most abundant source is palmitic acid (meat and palm oil), followed by stearic acid (cocoa), myristic acid (milk and coconut), and, in a small amount, lauric acid (coconut). The main dietary sources of palmitic acid are meat and palm oil.4242. Carta G, Murru E, Banni S, Manca C. Palmitic Acid: Physiological Role, Metabolism and Nutritional Implications. Front Physiol. 2017 Nov 8;8:902. , 4343. Orsavova J, Misurcova L, Ambrozova JV et al. Fatty acids composition of vegetable oils and its contribution to dietary energy intake and dependence of cardiovascular mortality on dietary intake of fatty acids. Int J Mol Sci. 2015; 16(6):12871-90.

2.4. Trans Fats

The main dietary source of trans fats is elaidic acid (18:1, n-9t), present in vegetable fats prepared from the partial hydrogenation of vegetable oils, which are widely used in the food industry.4444. Wolff RL, Precht D, Nasser B et al. Trans- and cis-octadecenoic acid isomers in the hump and milk lipids from Camelusdromedarius. Lipids. 2001;36(10):1175-8.Trans fat is also found, in small amounts, in meat and milk in the form of vaccenic acid (18:1, n-11t), which is synthesized by the biohydrogenation of fats under microbial action in ruminant animals.4444. Wolff RL, Precht D, Nasser B et al. Trans- and cis-octadecenoic acid isomers in the hump and milk lipids from Camelusdromedarius. Lipids. 2001;36(10):1175-8.

3. Plasma Concentration of Total Cholesterol and Lipoproteins

Reduced SFA intake is recommended because SFAs increase plasma LDLc concentrations.4545. Ference BA, Ginsberg HN, Graham I et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J. 2017; 38(32):2459-72.SFA intake has been shown to have a linear correlation with plasma lipid concentrations and to increase total cholesterol (TC), LDLc, and HDLc concentrations, as demonstrated in the WHO study.1111. Mensink RP. Effects of saturated fatty acids on serum lipids and lipoproteins: a systematic review and regression analysis. Geneva, Switzerland: World Health Organization; 2016.One of the publications of the Prospective Urban Rural Epidemiology (PURE) study, which investigated the association between diet and plasma lipids in more than 100 000 participants, also revealed an increased plasma concentration of TC, LDLc, and HDLc.4646. Mente A, Dehghan M, Rangarajan S et al. Prospective Urban Rural Epidemiology (PURE) study investigators. Association of dietary nutrients with blood lipids and blood pressure in 18 countries: a cross-sectional analysis from the PURE study. Lancet Diabetes Endocrinol. 2017; 5(10):774-87.The authors also showed a linear association between SFA intake and increased plasma lipids when comparing the highest quintile of intake (>11.2% of energy) to the lowest quintile (<4.03% of energy).

It is important to note that SFAs increase all lipoprotein classes, but the elevation observed in HDL may not be sufficient to overcome the deleterious effects of LDL on cardiovascular risk.4747. Foster GD, Wyatt HR, Hill JO et al. A randomized trial of a low-carbohydrate diet for obesity. N Engl J Med. 2003; 348(21):2082-90.The different SFAs exert different effects on the lipid profile and, therefore, on cardiovascular risk. Compared to carbohydrate, myristic acid (C14:0) produces the largest increases in the concentrations of TC and LDLc, followed by palmitic acid (C16:0) and lauric acid (C12:0), an effect not observed with stearic acid.1111. Mensink RP. Effects of saturated fatty acids on serum lipids and lipoproteins: a systematic review and regression analysis. Geneva, Switzerland: World Health Organization; 2016.The explanation is that stearic acid is rapidly converted to oleic acid in the liver by stearoyl-CoA desaturase-1 (SCD1).4848. Grundy SM. Influence of stearic acid on cholesterol metabolism relative to other long-chain fatty acids. Am J Clin Nutr. 1994; 60(6 Suppl):986S-90S.Regarding HDLc, myristic, lauric, and palmitic acids increase HDLc concentrations when isocalorically replacing carbohydrates.1111. Mensink RP. Effects of saturated fatty acids on serum lipids and lipoproteins: a systematic review and regression analysis. Geneva, Switzerland: World Health Organization; 2016.

SFAs act on plasma cholesterol by different mechanisms. In 1969, Spritz and Mishkel4949. Spritz N, Mishkel MA. Effects of dietary fats on plasma lipids and lipoproteins: an hypothesis for the lipid-lowering effect of unsaturated fatty acids. J Clin Invest. 1969; 48(1):78-86.demonstrated that, due to the straight carbon chain, SFAs can be packed in the core of lipoproteins, allowing them to carry a larger amount of cholesterol.4949. Spritz N, Mishkel MA. Effects of dietary fats on plasma lipids and lipoproteins: an hypothesis for the lipid-lowering effect of unsaturated fatty acids. J Clin Invest. 1969; 48(1):78-86.Later, it was demonstrated that SFAs, in combination with cholesterol, are able to reduce LDL receptor activity, protein, and mRNA,5050. Srivastava RA, Ito H, Hess M et al. Regulation of low-density lipoprotein receptor gene expression in HepG2 and Caco2 cells by palmitate, oleate, and 25-hydroxycholesterol. J Lipid Res.1995; 36(7):1434-46. , 5151. Mustad VA, Ellsworth JL, Cooper AD et al. Dietary linoleic acid increases and palmitic acid decreases hepatic LDL receptor protein and mRNA abundance in young pigs. J Lipid Res. 1996; 37(11):2310-23. thus impairing LDL clearance.5252. Nicolosi RJ, Stucchi AF, Kowala MC et al. Effect of dietary fat saturation and cholesterol on LDL composition and metabolism. In vivo studies of receptor and nonreceptor-mediated catabolism of LDL in cebus monkeys. Arteriosclerosis. 1990; 10(1):119-28 , 5353. Jackson KG, Maitin V, Leake DS et al. Saturated fat-induced changes in Sf 60-400 particle composition reduces uptake of LDL by HepG2 cells. J Lipid Res. 2006; 47(2):393-403. In addition, SFA intake increases the RNAm of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, phosphomevalonate kinase, and lanosterol synthase—important enzymes in the cholesterol synthesis pathway.5454. Lin J, Yang R, Tarr PT et al. Hyperlipidemic effects of dietary saturated fats mediated through PGC-1beta coactivation of SREBP. Cell. 2005; 120(2):261-73.

A study performed in the cohorts of the Nurses’ Health Study (NHS) (1984-2012) and Health Professionals Follow-up Study (HPFS) (1986-2010) showed that the isocaloric replacement of 1% energy from lauric, palmitic, or stearic acids with PUFAs or MUFAs reduced the risk of coronary heart disease.5555. Zong G, Li Y, Wanders AJ et al. Intake of individual saturated fatty acids and risk of coronary heart disease in US men and women: two prospective longitudinal cohort studies. BMJ. 2016 Nov; 355:i5796.This effect is associated with the impact of UFAs on plasma lipids, which reduces LDLc concentrations and may also reduce HDLc concentrations.5656. Mensink RP, Zock PL, Kester AD et al. Effects of dietary fatty acids and carbohydrates on the ratio of serum total to HDL cholesterol and on serum lipids and apolipoproteins: a meta-analysis of 60 controlled trials. Am J Clin Nutr 2003; 77(5):1146-55.A meta-analysis showed that, for each replacement of 1% energy from SFAs with PUFAs, there is a reduction in plasma concentrations of TC, LDLc, HDLc, apolipoprotein AI (ApoA-I), and apolipoprotein B (ApoB).5656. Mensink RP, Zock PL, Kester AD et al. Effects of dietary fatty acids and carbohydrates on the ratio of serum total to HDL cholesterol and on serum lipids and apolipoproteins: a meta-analysis of 60 controlled trials. Am J Clin Nutr 2003; 77(5):1146-55.When SFAs are isocalorically replaced with MUFAs, more modest reductions, although significant, are observed in plasma lipids, including TC, LDLc, HDLc, and ApoB.1111. Mensink RP. Effects of saturated fatty acids on serum lipids and lipoproteins: a systematic review and regression analysis. Geneva, Switzerland: World Health Organization; 2016.

A review of observational and intervention studies concluded that the replacement of SFAs with PUFAs reduces LDLc levels and, subsequently, CVD risk.5757. Schwab U, Lauritzen L, Tholstrup T et al. Effect of the amount and type of dietary fat on cardiometabolic risk factors and risk of developing type 2 diabetes, cardiovascular diseases, and cancer: a systematic review. Food Nutr Res. 2014; 10:58.A prospective cohort study involving 84 628 women and 42 908 men showed that the isocaloric replacement of SFAs (5% energy) with complex carbohydrates was associated with an 11% reduction in the risk of coronary heart disease.5858. Li Y, Hruby A, Bernstein AM et al. Saturated fats compared with unsaturated fats and sources of carbohydrates in relation to risk of coronary heart disease: a prospective cohort study. J Am Coll Cardiol. 2015; 66(14):1538-48.Conversely, the Women’s Health Initiative (WHI) intervention trial, which investigated the effect of reducing fat intake and increasing vegetable, fruit, and grain intakes on cardiovascular outcomes, reported that the dietary intervention had no effect on reducing cardiovascular risk.5959. Howard BV, Van Horn L, Hsia J et al. Low-fat dietary pattern and risk of cardiovascular disease: the Women’s Health Initiative Randomized Controlled Dietary Modification Trial. JAMA. 2006; 295(6):655-66.However, the intervention had only a mild effect on reducing LDLc levels and decreasing SFA intake (only 2.9% compared to controls). The reduction in total fat intake also reduced MUFA and PUFA intake.5959. Howard BV, Van Horn L, Hsia J et al. Low-fat dietary pattern and risk of cardiovascular disease: the Women’s Health Initiative Randomized Controlled Dietary Modification Trial. JAMA. 2006; 295(6):655-66.Moreover, the isocaloric replacement of SFAs with carbohydrates reduces TC, LDLc, HDLc, ApoA-I, and ApoB.1111. Mensink RP. Effects of saturated fatty acids on serum lipids and lipoproteins: a systematic review and regression analysis. Geneva, Switzerland: World Health Organization; 2016.

Two important meta-analyses of clinical trials showed a neutral effect of MUFAs on plasma lipid concentration.6060. Hegsted DM, Ausman LM, Johnson JA et al. Dietary fat and serum lipids: An evaluation of the experimental data. Am J Clin Nutr. 1993;57(6):875-83. , 6161. Gardner CD, Kraemer HC. Monounsaturated versus polyunsaturated dietary fat and serum lipids. A meta-analysis. Arterioscler. Arterioscler Thromb Vasc Biol. 1995; 15(11):1917-27. A recent systematic review and regression analysis of intervention studies showed that the replacement of 1% energy from SFAs with an equivalent amount of MUFAs significantly reduced the plasma concentrations of TC, LDLc, and HDLc.1111. Mensink RP. Effects of saturated fatty acids on serum lipids and lipoproteins: a systematic review and regression analysis. Geneva, Switzerland: World Health Organization; 2016.Conversely, the isocaloric replacement of carbohydrates with MUFAs increased HDLc levels, an effect that decreases with increasing unsaturation of fatty acids.6262. Mensink RP, Katan MB. Effect of dietary fatty acids on serum lipids and lipoproteins. A meta-analysis of 27 trials. Arterioscler Thromb. 1992; 12(8):911-9.Also, a diet rich in MUFAs (20% of energy) was shown to reduce the plasma concentration of TC, LDLc, small LDL particles, oxidized LDL, and HDLc.6363. Egert S, Kratz M, Kannenberg F et al. Effects of high-fat and low-fat diets rich in monounsaturated fatty acids on serum lipids, LDL size and indices of lipid peroxidation in healthy non-obese men and women when consumed under controlled conditions. Eur J Nutr. 2011; 50(1):71-9.In a study of overweight individuals, increased MUFA intake (from 7 to 13% of energy) also contributed to a reduction in TC and LDLc levels, but with no changes in HDLc.6464. Gill JM, Brown JC, Caslake MJ et al. Effects of dietary monounsaturated fatty acids on lipoprotein concentrations, compositions, and subfraction distributions and on VLDL apolipoprotein B kinetics: dose-dependent effects on LDL. Am J Clin Nutr. 2003; 78(1):47-56.Overall, adequate MUFA intake has shown a positive effect on lipid metabolism, with effects opposite to those of SFAs.

The replacement of 1% energy from SFAs with ω6 was shown to reduce TC by 2 mg/dL, with minimal impact on HDLc.5656. Mensink RP, Zock PL, Kester AD et al. Effects of dietary fatty acids and carbohydrates on the ratio of serum total to HDL cholesterol and on serum lipids and apolipoproteins: a meta-analysis of 60 controlled trials. Am J Clin Nutr 2003; 77(5):1146-55.An important meta-analysis of observational epidemiological studies points to the cholesterol-lowering effect of ω6 when replacing SFAs and trans fats in humans.5656. Mensink RP, Zock PL, Kester AD et al. Effects of dietary fatty acids and carbohydrates on the ratio of serum total to HDL cholesterol and on serum lipids and apolipoproteins: a meta-analysis of 60 controlled trials. Am J Clin Nutr 2003; 77(5):1146-55.The replacement of 10% energy from SFAs with ω6 was associated with a reduction of 18 mg/dL in LDLc levels, a greater impact than that observed with the isocaloric replacement of carbohydrates. In addition, the high plasma concentration of ω6 was associated with a reduction in the TC/HDLc ratio.5656. Mensink RP, Zock PL, Kester AD et al. Effects of dietary fatty acids and carbohydrates on the ratio of serum total to HDL cholesterol and on serum lipids and apolipoproteins: a meta-analysis of 60 controlled trials. Am J Clin Nutr 2003; 77(5):1146-55.

Increased ω6 intake was associated with a small reduction in plasma TC concentration, and only minimal or no effect was observed in HDLc and LDLc concentrations. Therefore, current evidence is insufficient to propose ω6 supplementation for the primary and secondary prevention of CVD.6565. Hooper L, Al-Khudairy L, Abdelhamid AS et al. Omega-6 fats for the primary and secondary prevention of cardiovascular disease. Cochrane Database Syst Rev. 2018 Nov;11:CD011094.

With regard to ω3 fatty acids, the results of a systematic review showed inconsistent data on the effect of ALA on plasma cholesterol.6666. Balk EM, Lichtenstein AH, Chung M et al. Effects of omega-3 fatty acids on serum markers of cardiovascular disease risk: a systematic review. Atherosclerosis. 2006; 189(1):19-30.A meta-analysis of randomized trials found no significant influence of ALA supplementation on TC and LDLc levels, with minimal effect on HDLc (reduction of 0.4 mg/dL).6767. Wendland E, Farmer A, Glasziou P et al. Effect of alpha linolenic acid on cardiovascular risk markers: a systematic review. Heart. 2006; 92(2):166-9.DHA, however, was associated with elevated LDLc,6666. Balk EM, Lichtenstein AH, Chung M et al. Effects of omega-3 fatty acids on serum markers of cardiovascular disease risk: a systematic review. Atherosclerosis. 2006; 189(1):19-30.and the same result was observed with fish-oil supplementation.6868. Harris WS, Miller M, Tighe AP et al. Omega-3 fatty acids and coronary heart disease risk: clinical and mechanistic perspectives. Atherosclerosis 2008;197(1):12-24This increase in cholesterol is probably attributable to the decreased expression of sterol regulatory element-binding protein 2 (SREBP-2), which regulates the LDL receptor synthesis,6969. Ishida T, Ohta M, Nakakuki M et al. Distinct regulation of plasma LDL cholesterol by eicosapentaenoic acid and docosahexaenoic acid in high fat diet-fed hamsters: participation of cholesterol ester transfer protein and LDL receptor. Prostaglandins Leukot Essent Fatty Acids. 2013; 88(4):281-8 , 7070. Le Jossic-Corcos C, Gonthier C, Zaghini I et al. Hepatic farnesyl diphosphate synthase expression is suppressed by polyunsaturated fatty acids. Biochem J. 2005; 385(Pt 3):787-94. induced in a dose-dependent manner by DHA.

Another study showed that ALA-rich or EPA/DHA-rich diets did not promote changes in the lipid profile compared to a MUFA-rich diet.7171. Goyens PL, Mensink RP. Effects of alpha-linolenic acid versus those of EPA/DHA on cardiovascular risk markers in healthy elderly subjects. Eur J Clin Nutr. 2006;60(8): 978-84A similar result was obtained with oils enriched with EPA, DHA, and ALA.7272. Egert S, Somoza V, Kannenberg F et al. Influence of three rapeseed oil-rich diets, fortified with alpha-linolenic acid, eicosapentaenoic acid or docosahexaenoic acid on the composition and oxidizability of low-density lipoproteins: Results of a controlled study in healthy volunteers. Eur J Clin Nutr. 2007; 61(3):314-25.In this study, a beneficial effect on plasma lipids was observed only in the wash-in period, when the participants who had a SFA-rich diet received a MUFA-rich diet.7272. Egert S, Somoza V, Kannenberg F et al. Influence of three rapeseed oil-rich diets, fortified with alpha-linolenic acid, eicosapentaenoic acid or docosahexaenoic acid on the composition and oxidizability of low-density lipoproteins: Results of a controlled study in healthy volunteers. Eur J Clin Nutr. 2007; 61(3):314-25.It is important to note that, when analyzing the effects of ω3 fatty acids on cholesterolemia, the type of comparison made in the study should be considered, because UFAs, when used as a substitute in SFA-rich diets, promote beneficial effects; supplementation, however, shows different results.

Trans fatty acids have a greater atherogenic effect, due to their strong impact on cholesterolemia.7373. Machado RM, Nakandakare ER, Quintao EC et al. Omega-6 polyunsaturated fatty acids prevent atherosclerosis development in LDLr-KO mice, in spite of displaying a pro-inflammatory profile similar to trans fatty acids. Atherosclerosis. 2012; 224(1):66-74.An important meta-analysis of randomized controlled trials showed the deleterious actions of these fatty acids on the plasma concentrations of TC, LDLc, and VLDLc.5656. Mensink RP, Zock PL, Kester AD et al. Effects of dietary fatty acids and carbohydrates on the ratio of serum total to HDL cholesterol and on serum lipids and apolipoproteins: a meta-analysis of 60 controlled trials. Am J Clin Nutr 2003; 77(5):1146-55.Furthermore, trans fatty acids exert an additional adverse effect by reducing plasma HDLc concentrations compared to SFAs.7474. Matthan NR, Ausman LM, Lichtenstein AH et al. Hydrogenated fat consumption affects cholesterol synthesis in moderately hypercholesterolemic women. J Lipid Res. 2000; 41(5):834-9.

75. Matthan NR, Welty FK, Barrett PH et al. Dietary hydrogenated fat increases high-density lipoprotein apoA-I catabolism and decreases low-density lipoprotein apoB-100 catabolism in hypercholesterolemic women. Arterioscler Thromb Vasc Biol. 2004;24(6):1092-7.

76. Mozaffarian D, Katan MB, Ascherio A et al. Trans fatty acids and cardiovascular disease. N Engl J Med. 2006; 354(15):1601.
- 7777. Hadj Ahmed S, Kharroubi W, Kaoubaa N et al. Correlation of trans fatty acids with the severity of coronary artery disease lesions. Lipids Health Dis. 2018; 17(1):52. The reduction in HDLc results from the increased catabolism of ApoA-I.7474. Matthan NR, Ausman LM, Lichtenstein AH et al. Hydrogenated fat consumption affects cholesterol synthesis in moderately hypercholesterolemic women. J Lipid Res. 2000; 41(5):834-9. , 7575. Matthan NR, Welty FK, Barrett PH et al. Dietary hydrogenated fat increases high-density lipoprotein apoA-I catabolism and decreases low-density lipoprotein apoB-100 catabolism in hypercholesterolemic women. Arterioscler Thromb Vasc Biol. 2004;24(6):1092-7. Also, trans fatty acids increase the activity of cholesteryl ester transfer protein (CETP), a protein involved in the transfer of cholesteryl esters (CEs) and triglycerides (TGs) among plasma lipoproteins, thus enriching ApoB-rich particles with CEs. On the other hand, HDL particles become richer in TGs, favoring their catabolism.7878. Khosla P, Hajri T, Pronczuk A et al. Replacing dietary palmitic acid with elaidic acid (t-C18:1 delta9) depresses HDL and increases CETP activity in cebus monkeys. J Nutr. 1997; 127(3):531S-6S.Trans fat also acts deleteriously by reducing the clearance of ApoB100-containing particles, thus increasing its concentration in plasma,7575. Matthan NR, Welty FK, Barrett PH et al. Dietary hydrogenated fat increases high-density lipoprotein apoA-I catabolism and decreases low-density lipoprotein apoB-100 catabolism in hypercholesterolemic women. Arterioscler Thromb Vasc Biol. 2004;24(6):1092-7.which contributes to the formation of small, dense LDL particles that are more atherogenic.7979. Mauger JF, Lichtenstein AH, Ausman LM et al. Effect of different forms of dietary hydrogenated fats on LDL particle size. Am J Clin Nutr. 2003; 78(3):370-5.A meta-analysis of randomized controlled trials showed that, each 1% energy replacement of TRANS fat with SFAs, MUFAs or PUFAs, decreased the total cholesterol/ HDL-C and the ApoB/ApoAI ratio.8080. Mozaffarian D, Clarke R. Quantitative effects on cardiovascular risk factors and coronaryheart disease risk of replacing partially hydrogenated vegetable oils with other fats and oils. Eur J Clin Nutr. 2009; 63(Suppl 2):S22-33.Therefore, given the recognized negative impact of trans fats on the lipid profile, national and international guidelines recommend their exclusion from the diet.77. U.S. Department of Health and Human Services and U.S. Department of Agriculture. 2015 – 2020 Dietary Guidelines for Americans. 8th ed Dec, 2015. , 88. Eckel RH, Jakicic JM, Ard JD et al; American College of Cardiology/American Heart Association Task Force on Practice Guidelines. 2013 AHA/ACC guideline on lifestyle management to reduce cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014; 129(25 Suppl 2):S76-99. , 2020. Brasil. Ministério da Saúde. Secretaria de Atenção à Saúde. Departamento de Atenção Básica. Guia alimentar para a população brasileira / Ministério da Saúde, Secretaria de Atenção à Saúde, Departamento de Atenção Básica. 2. ed., 1. reimpr. Brasília: 2014. pp. 156.

4. Plasma Concentration of Triglycerides

Fatty acids act differently on triglyceridemia by modulating transcription factors that participate in the synthesis of lipogenic enzymes involved in fatty acid production.

SFAs are able to modulate genes involved in lipid synthesis. SFAs have been shown to induce the hepatic expression of peroxisome proliferator-activated receptor gamma coactivator 1β (PGC-1β), which in turn activates SREBP, a transcription factor involved in gene transcription of lipogenic enzymes such as acetyl-CoA carboxylase-1 and fatty acid synthase,8181. Harris WS, Bulchandani D. why do omega-3 fatty acids lower serum triglycerides? Curr Opin Lipidol. 2006; 17(4):387-93.related to fatty acid synthesis, favoring greater TG production.5454. Lin J, Yang R, Tarr PT et al. Hyperlipidemic effects of dietary saturated fats mediated through PGC-1beta coactivation of SREBP. Cell. 2005; 120(2):261-73.In addition, SFAs increase SREBP processing and its translocation to the cell nucleus, inducing the transcription of target genes.8282. Gale SE, Westover EJ, Dudley N et al. Side chain oxygenated cholesterol regulates cellular cholesterol homeostasis through direct sterol-membrane interactions. J Biol Chem. 2009;284(3):1755-64.

A systematic review published by the WHO1111. Mensink RP. Effects of saturated fatty acids on serum lipids and lipoproteins: a systematic review and regression analysis. Geneva, Switzerland: World Health Organization; 2016.showed that, for each replacement of 1% energy from SFAs with PUFAs or MUFAs, there was a reduction in plasma TG concentration (0.88 mg/dL and 0.35 mg/dL, respectively). The replacement of SFAs with carbohydrates, however, increased plasma TG concentration by 0.97 mg/dL.1111. Mensink RP. Effects of saturated fatty acids on serum lipids and lipoproteins: a systematic review and regression analysis. Geneva, Switzerland: World Health Organization; 2016.Conversely, it is known that PUFAs are involved in the reduction of plasma TG concentration by blocking SREBP, with a more pronounced effect exerted by ω3 fatty acids.8383. Hernández-Rodas MC, Valenzuela R, Echeverría F et al. Supplementation with docosahexaenoic acid and extra virgin olive oil prevents liver steatosis induced by a high-fat diet in mice through PPAR-α and Nrf2 upregulation with concomitant SREBP-1c and NF-kB downregulation. Mol Nutr Food Res. 2017;61(12).

Regarding the action of ALA on triglyceridemia, an experimental study in animals observed a null to mild effect with the use of flaxseed.8484. Prasad K. Flaxseed and cardiovascular health. J Cardiovasc Pharmacol. 2009; 54(5):369-77.In humans, a systematic review showed that the TG-lowering effect results from the intake of large amounts of flaxseed oil.6666. Balk EM, Lichtenstein AH, Chung M et al. Effects of omega-3 fatty acids on serum markers of cardiovascular disease risk: a systematic review. Atherosclerosis. 2006; 189(1):19-30.A meta-analysis of 14 randomized controlled trials observed no significant effect of ALA supplementation on plasma TG concentrations.6767. Wendland E, Farmer A, Glasziou P et al. Effect of alpha linolenic acid on cardiovascular risk markers: a systematic review. Heart. 2006; 92(2):166-9.Similarly, increased ω6 intake was not associated with decreased plasma TG concentrations.6565. Hooper L, Al-Khudairy L, Abdelhamid AS et al. Omega-6 fats for the primary and secondary prevention of cardiovascular disease. Cochrane Database Syst Rev. 2018 Nov;11:CD011094.

Clinical studies show that supplementation with 2 to 4 g/day of EPA and DHA can reduce plasma TG concentration by 25 to 30%.6666. Balk EM, Lichtenstein AH, Chung M et al. Effects of omega-3 fatty acids on serum markers of cardiovascular disease risk: a systematic review. Atherosclerosis. 2006; 189(1):19-30. , 8585. Harris WS. n-3 fatty acids and serum lipoproteins: human studies. Am J Clin Nutr. 1997; 65(5 Suppl):1645S-54S. , 8686. Hartweg J, Perera R, Montori V et al. Omega-3 polyunsaturated fatty acids (PUFA) for type 2 diabetes mellitus. Cochrane Database Syst Rev. 2008 Jan;(1):CD003205. A 4-week EPA or DHA supplementation in healthy subjects reduced the postprandial concentrations of TG, ApoB48, and ApoB100 (16%, 28%, and 24%, respectively), possibly due to the increased activity of lipoprotein lipase (LPL).8787. Park Y, Harris WS. Omega-3 fatty acid supplementation accelerates chylomicron triglyceride clearance. J. Lipid Res. 2003; 44(3):455-63.

The triglyceride-lowering effect of PUFAs is related to their ability to reduce SREBP1 expression and activity.8181. Harris WS, Bulchandani D. why do omega-3 fatty acids lower serum triglycerides? Curr Opin Lipidol. 2006; 17(4):387-93.In animal models and in vitro studies, both EPA and DHA decreased SREBP1, reducing the expression of lipogenic enzymes.8888. Caputo M, Zirpoli H, Torino G et al. Selective regulation of UGT1A1 and SREBP-1c mRNA expression by docosahexaenoic, eicosapentaenoic, and arachidonic acids. J Cell Physiol. 2011;226(1):187-93. , 8989. Howell G, Deng X, Yellaturu C et al. n-3 polyunsaturated fatty acids suppress insulin-induced SREBP-1c transcription via reduced trans-activating capacity of LXR-alpha. Biochim Biophys Acta. 2009; 1791(12):1190-6. , 9090. Kajikawa S, Harada T, Kawashima A et al. Highly purified eicosapentaenoic acid prevents the progression of hepatic steatosis by repressing monounsaturated fatty acid synthesis in high-fat/high-sucrose diet-fed mice. Prostaglandins Leukot Essent Fatty Acids. 2009; 80(4):229-38.

The ability of ω3 fatty acids to reduce TGs appears to be dose-dependent, with reductions of about 5 to 10% for each 1 g of EPA/DHA consumed daily, being greater in individuals with higher baseline TG concentrations.9191. Miller M, Stone NJ, Ballantyne C et al; American Heart Association Clinical Lipidology, Thrombosis, and Prevention Committee of the Council on Nutrition, Physical Activity, and Metabolism, Council on Arteriosclerosis, Thrombosis and Vascular Biology, Council on Cardiovascular N. Triglycerides and cardiovascular disease: a scientific statement from the American Heart Association. Circulation. 2011; 123(20):2292-333.

92. Jacobson TA. Role of n-3 fatty acids in the treatment of hypertriglyceridemia and cardiovascular disease. Am J Clin Nutr. 2008; 87(6):1981S-90S.
- 9393. Mente A, de Koning L, Shannon HS et al. A systematic review of the evidence supporting a causal link between dietary factors and coronary heart disease. Arch Intern Med. 2009; 169(7):659-69. A study of individuals with borderline or high TG values who received 1 to 4 g/day of krill oil for 6 weeks showed a reduction in plasma TG concentrations (18.6 to 19.9 mg/dL). With a supplementation of 0.5 g/day of krill oil, the reduction in TG levels was 13.3 mg/dL.3636. Berge K, Musa-Veloso K, Harwood M et al. Krill oil supplementation lowers triglycerides without increasing low-density lipoprotein cholesterol in adults with borderline high or high triglyceride levels. Nutr Res. 2014;34(2):126-33.

5. Cardiovascular and Coronary Heart Disease

5.1. Saturated Fatty Acids

Despite the important biological activities of SFAs, high SFA intake has a deleterious effect on lipid metabolism and cardiovascular risk,9494. Mozaffarian D, Micha R, Wallace S. Effects on coronary heart disease of increasing polyunsaturated fat in place of saturated fat: a systematic review and meta-analysis of randomized controlled trials. PLoS Med. 2010; 7(3):e1000252. , 9595. Astrup A, Dyerberg J, Elwood P et al. The role of reducing intakes of saturated fat in the prevention of cardiovascular disease: where does the evidence stand in 2010? Am J Clin Nutr. 2011; 93(4):684-8. as they increase plasma LDLc concentrations, which is one of the main risk factors for the development of atherosclerosis and, consequently, CVD.1111. Mensink RP. Effects of saturated fatty acids on serum lipids and lipoproteins: a systematic review and regression analysis. Geneva, Switzerland: World Health Organization; 2016.A comprehensive systematic review conducted by the Cochrane Library, in 2015, showed that decreased SFA intake was able to reduce cardiovascular events by 17%, compared to usual diet.9696. Hooper L, Martin N, Abdelhamid A et al. Reduction in saturated fat intake for cardiovascular disease. Cochrane Database Syst Rev. 2015 Jun; (6):CD011737.In addition, in the same meta-analysis subgrouping the studies that replaced SFAs with PUFAs showed a 27% reduction in cardiovascular events. For this reason, nutritional recommendations to reduce cardiovascular risk include reducing SFA intake.

However, in recent years, meta-analyses and observational studies have drawn conflicting conclusions about the relationship between SFA intake and cardiovascular risk.1212. Siri-Tarino PW, Sun Q, Hu FB et al. Saturated fat, carbohydrate, and cardiovascular disease. Am J Clin Nutr. 2010;91(3):502-9. , 9494. Mozaffarian D, Micha R, Wallace S. Effects on coronary heart disease of increasing polyunsaturated fat in place of saturated fat: a systematic review and meta-analysis of randomized controlled trials. PLoS Med. 2010; 7(3):e1000252. , 9696. Hooper L, Martin N, Abdelhamid A et al. Reduction in saturated fat intake for cardiovascular disease. Cochrane Database Syst Rev. 2015 Jun; (6):CD011737. , 9797. Farvid MS, Ding M, Pan A et al. Dietary linoleic acid and risk of coronary heart disease: a systematic review and meta-analysis of prospective cohort studies. Circulation. 2014; 130(16):1568-78.

98. Chowdhury R, Warnakula S, Kunutsor S et al. Association of dietary, circulating, and supplement fatty acids with coronary risk: a systematic review and meta-analysis. Ann Intern Med. 2014;160(6):398-406.
- 9999. Jakobsen MU, O’Reilly EJ, Heitmann BL et al. Major types of dietary fat and risk of coronary heart disease: a pooled analysis of 11 cohort studies. Am J Clin Nutr. 2009;89(5):1425-32. This discrepancy is due, in part, to the macronutrient used for SFA replacement, since a reduction in one dietary macronutrient leads to an increase in another.100100. Zelman K. The great fat debate: a closer look at the controversy-questioning the validity of age-old dietary guidance. J Am Diet Assoc. 2011; 111(5):655-8.Meta-analyses of prospective observational studies assessing the effect of SFAs on the occurrence of cardiovascular events, without considering the type of macronutrient used for SFA replacement, observed no effect of SFA intake on cardiovascular risk.9898. Chowdhury R, Warnakula S, Kunutsor S et al. Association of dietary, circulating, and supplement fatty acids with coronary risk: a systematic review and meta-analysis. Ann Intern Med. 2014;160(6):398-406. , 101101. Siri-Tarino PW, Sun Q, Hu FB et al. Meta-analysis of prospective cohort studies evaluating the association of saturated fat with cardiovascular disease. Am J Clin Nutr 2010; 91(3):535-46. Conversely, the replacement of SFAs with PUFAs or complex carbohydrates from whole grains proved to be beneficial and was associated with a lower risk of coronary heart disease. The replacement of SFAs with simple carbohydrates, however, had no impact on the risk of cardiovascular events,9797. Farvid MS, Ding M, Pan A et al. Dietary linoleic acid and risk of coronary heart disease: a systematic review and meta-analysis of prospective cohort studies. Circulation. 2014; 130(16):1568-78. , 9999. Jakobsen MU, O’Reilly EJ, Heitmann BL et al. Major types of dietary fat and risk of coronary heart disease: a pooled analysis of 11 cohort studies. Am J Clin Nutr. 2009;89(5):1425-32. since high sugar intake has a detrimental effect on cardiovascular health.

The PURE study, conducted in 18 countries, evaluated the association of dietary components with total mortality and cardiovascular events and showed that the risk of total mortality and non-CVD mortality was positively associated with higher carbohydrate intake and negatively associated with higher intakes of fat (PUFAs, MUFAs, and SFAs) and proteins (% of energy). It is worth noting that the highest fat and SFA intake was 35% and 13% of energy, respectively, and the highest carbohydrate intake median reached 77% of energy. In addition, increased SFA intake was associated with a lower risk of stroke. Total fat intake, as well as SFA and UFA intake, was not associated with myocardial infarction risk or CVD mortality.102102. Dehghan M, Mente A, Zhang X et al. Prospective Urban Rural Epidemiology (PURE) study investigators. Associations of fats and carbohydrate intake with cardiovascular disease and mortality in 18 countries from five continents (PURE): a prospective cohort study. Lancet. 2017; 390(10107):2050-62.The type of carbohydrate consumed was not analyzed separately, but it was observed that, in low-income and middle-income countries, people consumed carbohydrates mainly from refined sources. Further analysis showed that total fat and SFA intake correlated with increased plasma concentrations of TC and LDLc.4646. Mente A, Dehghan M, Rangarajan S et al. Prospective Urban Rural Epidemiology (PURE) study investigators. Association of dietary nutrients with blood lipids and blood pressure in 18 countries: a cross-sectional analysis from the PURE study. Lancet Diabetes Endocrinol. 2017; 5(10):774-87.In 2018, in that same cohort, dairy intake was shown to be negatively associated with total and CVD mortality, CVD, and stroke.103103. Dehghan M, Mente A, Rangarajan S et al; Prospective Urban Rural Epidemiology (PURE) study investigators. Association of dairy intake with cardiovascular disease and mortality in 21 countries from five continents (PURE): a prospective cohort study. Lancet. 2018; 392(10161):2288-97.

Randomized studies have evaluated the effects of dietary interventions on the occurrence of cardiovascular events; however, the differences in total fat intake between the intervention and control groups were not substantial in most studies.5959. Howard BV, Van Horn L, Hsia J et al. Low-fat dietary pattern and risk of cardiovascular disease: the Women’s Health Initiative Randomized Controlled Dietary Modification Trial. JAMA. 2006; 295(6):655-66. , 104104. Hjermann I, Velve Byre K, Holme I et al. Effect of diet and smoking intervention on the incidence of coronary heart disease. Report from the Oslo Study Group of a randomised trial in healthy men. Lancet. 1981; 2(8259):1303. , 105105. Anderson CA, Appel LJ. Dietary modification and CVD prevention: a matter of fat. JAMA. 2006; 295(6):693. The WHI trial followed, for about 8 years, 48 835 women who were randomly assigned to either dietary modification (reducing fat intake to 20% of energy and increasing vegetable and grain intakes) or to a control group (guidance through diet-related education materials). After 6 years of follow-up, the dietary intervention did not reduce the occurrence of coronary artery disease (CAD) or stroke, despite the significant reduction in total fat intake.5959. Howard BV, Van Horn L, Hsia J et al. Low-fat dietary pattern and risk of cardiovascular disease: the Women’s Health Initiative Randomized Controlled Dietary Modification Trial. JAMA. 2006; 295(6):655-66.

A prospective cohort study showed that higher SFA intake was associated with a lower risk of ischemic heart disease, but not with the risk of coronary heart disease.106106. Praagman J, Beulens JW, Alssema M et al. The association between dietary saturated fatty acids and ischemic heart disease depends on the type and source of fatty acid in the European Prospective Investigation into Cancer and Nutrition-Netherlands cohort. Am J Clin Nutr 2016; 103(2):356-65.In another cohort, the intake of palmitic acid, but not of total SFAs, was positively associated with the risk of CAD.107107. Praagman J, de Jonge EA, Kiefte-de Jong JC et al. Dietary saturated fatty acids and coronary heart disease risk in a Dutch middle-aged and elderly population. Arterioscler Thromb Vasc Biol 2016; 36(9):2011-8.

Recent studies have shown that different types of SFAs have heterogeneous cardiometabolic effects and correlate differently with cardiovascular risk, coronary heart disease, and the incidence of type 2 diabetes (T2D). In this context, lauric, myristic, palmitic, and stearic acids are associated with an increased risk of coronary heart disease5555. Zong G, Li Y, Wanders AJ et al. Intake of individual saturated fatty acids and risk of coronary heart disease in US men and women: two prospective longitudinal cohort studies. BMJ. 2016 Nov; 355:i5796. , 108108. Khaw KT, Friesen MD, Riboli E et al. Plasma phospholipid fatty acid concentration and incident coronary heart disease in men and women: the EPIC-Norfolk prospective study. PLoS Med. 2012; 9(7):e1001255. and T2D,1414. Forouhi NG, Koulman A, Sharp SJ et al. Differences in the prospective association between individual plasma phospholipid saturated fatty acids and incident type 2 diabetes: the EPIC-InterAct case-cohort study. Lancet Diabetes Endocrinol. 2014; 2(10):810-8. , 109109. Imamura F, Sharp SJ, Koulman A et al. A combination of plasma phospholipid fatty acids and its association with incidence of type 2 diabetes: The EPIC-InterAct case-cohort study. PLoS Med. 2017; 14(10):e1002409. whereas pentadecanoid acid (15:0)110110. de Oliveira Otto MC, Nettleton JA, Lemaitre RN et al. Biomarkers of dairy fatty acids and risk of cardiovascular disease in the Multi-ethnic Study of Atherosclerosis. J Am Heart Assoc. 2013; 2(4):e000092.and margaric acid (c17:0) are associated with the intake of dairy products, and long-chain SFAs (20:0 to 24:0) correlate inversely with the incidence of CVD and T2D.1414. Forouhi NG, Koulman A, Sharp SJ et al. Differences in the prospective association between individual plasma phospholipid saturated fatty acids and incident type 2 diabetes: the EPIC-InterAct case-cohort study. Lancet Diabetes Endocrinol. 2014; 2(10):810-8. , 110110. de Oliveira Otto MC, Nettleton JA, Lemaitre RN et al. Biomarkers of dairy fatty acids and risk of cardiovascular disease in the Multi-ethnic Study of Atherosclerosis. J Am Heart Assoc. 2013; 2(4):e000092.

5.2. Replacement of Saturated with Unsaturated Fatty Acids

A prospective cohort study that investigated 83 349 women and 42 884 men, from 1986 to 2012, showed that the isocaloric replacement of 5% energy from SFAs with MUFAs or PUFAs was associated with an estimated decrease in total mortality by 13% and 27%, respectively. In addition, the replacement of SFAs with PUFAs reduced the risk of death from CVD, cancer, and neurodegenerative diseases.9393. Mente A, de Koning L, Shannon HS et al. A systematic review of the evidence supporting a causal link between dietary factors and coronary heart disease. Arch Intern Med. 2009; 169(7):659-69.Intervention studies have shown that the isocaloric replacement of 10% energy from SFAs with PUFAs reduces the risk of cardiovascular events by 27%,111111. Reedy J, Krebs-Smith SM, Miller PE et al. Higher diet quality is associated with decreased risk of allcause, cardiovascular disease, and cancer mortality among older adults. J Nutr. 2014; 144(6):881-9.and 5% replacement reduces the risk of CAD by 10%.9494. Mozaffarian D, Micha R, Wallace S. Effects on coronary heart disease of increasing polyunsaturated fat in place of saturated fat: a systematic review and meta-analysis of randomized controlled trials. PLoS Med. 2010; 7(3):e1000252.The isocaloric replacement (1% of energy) of SFAs (12:0 to 18:0) with complex carbohydrates reduced the risk of coronary heart disease, as demonstrated in the analysis of the HPFS and NHS studies.5555. Zong G, Li Y, Wanders AJ et al. Intake of individual saturated fatty acids and risk of coronary heart disease in US men and women: two prospective longitudinal cohort studies. BMJ. 2016 Nov; 355:i5796.

5.3. Replacement of Saturated Fatty Acids with Carbohydrates

A prospective cohort study involving 84 628 women and 42 908 men showed that the isocaloric replacement of SFAs (5% energy) with complex carbohydrates was associated with an 11% reduction in the risk of coronary heart disease.5858. Li Y, Hruby A, Bernstein AM et al. Saturated fats compared with unsaturated fats and sources of carbohydrates in relation to risk of coronary heart disease: a prospective cohort study. J Am Coll Cardiol. 2015; 66(14):1538-48.Likewise, the isocaloric replacement of only 1% energy in the form of SFAs (12:0 to 18:0) with complex carbohydrates reduced the risk of coronary heart disease.5555. Zong G, Li Y, Wanders AJ et al. Intake of individual saturated fatty acids and risk of coronary heart disease in US men and women: two prospective longitudinal cohort studies. BMJ. 2016 Nov; 355:i5796.

Conversely, an intervention study evaluating the effect of reducing fat intake and increasing vegetable, fruit, and grain intakes on cardiovascular outcomes observed no effect of diet on reducing cardiovascular risk.5959. Howard BV, Van Horn L, Hsia J et al. Low-fat dietary pattern and risk of cardiovascular disease: the Women’s Health Initiative Randomized Controlled Dietary Modification Trial. JAMA. 2006; 295(6):655-66.However, the intervention had only a mild effect on reducing LDLc levels (2.7 mg/dL) and decreasing SFA intake (only 2.9% compared to controls). It is worth noting that the reduction in total fat intake also reduced MUFA and PUFA intakes, which are associated with a favorable lipid profile from a cardiovascular point of view.5959. Howard BV, Van Horn L, Hsia J et al. Low-fat dietary pattern and risk of cardiovascular disease: the Women’s Health Initiative Randomized Controlled Dietary Modification Trial. JAMA. 2006; 295(6):655-66.

Regarding plasma lipids, isocaloric replacement of SFAs with carbohydrates reduces TC (1.58 mg/dL), LDLc (1.27 mg/dL), HDLc (0.38 mg/dL), ApoA-I (7.0 mg/dL), and ApoB (3.6 mg/dL), whereas it increases TG concentrations (0.97 mg/dL).1111. Mensink RP. Effects of saturated fatty acids on serum lipids and lipoproteins: a systematic review and regression analysis. Geneva, Switzerland: World Health Organization; 2016.

With regard to MUFAs, several studies based on a Mediterranean diet have shown positive effects in the prevention of cardiovascular risk factors and outcomes. Olive oil is the main source of MUFAs in the Mediterranean diet, followed by walnuts and chestnuts, which also provide PUFAs. It should be noted that this dietary pattern includes vegetables, fruits, and grains, which are also beneficial for cardiovascular health.112112. Casas R, Urpi-Sardà M, Sacanella E et al. anti-inflammatory effects of the Mediterranean diet in the early and late stages of atheroma plaque development. Mediators Inflamm. 2017 Apr; 2017:3674390.

The PREDIMED study followed for 5 years more than 5000 participants at high cardiovascular risk who were assigned to a Mediterranean diet supplemented with extra-virgin olive oil (50 g/day) or mixed nuts (30 g/day), both compared to control participants who consumed a diet with less fat content (30% of energy). The results showed that both intervention groups had fewer cardiovascular events (RR = 0.83).1717. Estruch R, Ros E, Salas-Salvadó J et al. Primary prevention of cardiovascular disease with a Mediterranean diet supplemented with extra-virgin olive oil or nuts. N Engl J Med. 2018; 378(25):e34.Similar results were also observed with olive oil intake in the NHS study (1980-2010, n = 84 628, HR = 0.85), HPFS study (1986-2010, n = 42 908, HR = 0.85), Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (RR = 0.92), and European Prospective Investigation into Cancer and Nutrition (EPIC) study (HR = 0.87).113113. Joris PJ, Mensink RP. Role of cis-monounsaturated fatty acids in the prevention of coronary heart disease. Curr Atheroscler Rep. 2016; 18(7):38.One of the arms of the EPIC study, conducted in the Dutch population, showed an increased risk of ischemic heart disease associated with MUFA intake (HR = 1.30).106106. Praagman J, Beulens JW, Alssema M et al. The association between dietary saturated fatty acids and ischemic heart disease depends on the type and source of fatty acid in the European Prospective Investigation into Cancer and Nutrition-Netherlands cohort. Am J Clin Nutr 2016; 103(2):356-65.However, it is worth noting that the authors of this study identified important confounding factors that could interfere with the final interpretation of the outcome, as they did not distinguish between cis and trans MUFAs.106106. Praagman J, Beulens JW, Alssema M et al. The association between dietary saturated fatty acids and ischemic heart disease depends on the type and source of fatty acid in the European Prospective Investigation into Cancer and Nutrition-Netherlands cohort. Am J Clin Nutr 2016; 103(2):356-65.

A review of studies published by the Cochrane Collaboration showed that the effectiveness of replacing SFAs with MUFAs in cardiovascular events is uncertain due to the small number of studies included.9696. Hooper L, Martin N, Abdelhamid A et al. Reduction in saturated fat intake for cardiovascular disease. Cochrane Database Syst Rev. 2015 Jun; (6):CD011737.The Dietary Guidelines for Americans,77. U.S. Department of Health and Human Services and U.S. Department of Agriculture. 2015 – 2020 Dietary Guidelines for Americans. 8th ed Dec, 2015.however, state that the replacement of SFAs with MUFAs is associated with reduced cardiovascular risk, although the evidence is not so strong. A later cohort study showed that the replacement of 5% energy from SFAs with MUFAs reduced cardiovascular risk by 15%.5858. Li Y, Hruby A, Bernstein AM et al. Saturated fats compared with unsaturated fats and sources of carbohydrates in relation to risk of coronary heart disease: a prospective cohort study. J Am Coll Cardiol. 2015; 66(14):1538-48.

5.4. Polyunsaturated Fatty Acids (Omega-6)

Regarding the effects ω6 series of UFAs on cardiovascular risk, randomized controlled trials and observational studies have provided evidence that the replacement of about 5 to 10% energy in the form of SFAs and refined carbohydrates (such as sugar, white bread, white rice) with ω6 reduces the risk of CVD without clinical evidence of adverse events.114114. Harris WS, Poston WC, Haddock CK. Tissue n-3 and n-6 fatty acids and risk for coronary heart disease events. Atherosclerosis. 2007; 193(1):1-10.

115. Miettinen M, Turpeinen O, Karvonen MJ et al. Dietary prevention of coronary heart disease in women: the Finnish mental hospital study. Int J Epidemiol. 1983;12(1):17-25.

116. Frantz ID Jr, Dawson EA, Ashman PL et al. Test of effect of lipid lowering by diet on cardiovascular risk: the Minnesota Coronary Survey. Arteriosclerosis. 1989; 9(1):129-35.
- 117117. Kris-Etherton P, Fleming J, Harris WS. The debate about n-6 polyunsaturated fatty acid recommendations for cardiovascular health. J Am Diet Assoc. 2010; 110(2):201-4. The replacement of 1% energy from SFAs with ω6 has been associated with a reduction of 2 to 3% in the incidence of coronary heart disease.9494. Mozaffarian D, Micha R, Wallace S. Effects on coronary heart disease of increasing polyunsaturated fat in place of saturated fat: a systematic review and meta-analysis of randomized controlled trials. PLoS Med. 2010; 7(3):e1000252. , 118118. Lloyd-Williams F, O’Flaherty M, Mwatsama M et al. Estimating the cardiovascular mortality burden attributable to the European Common Agricultural Policy on dietary saturated fats. Bull World Health Organ. 2008; 86(7):535-41A. This benefit may even be underestimated due to the large amount of SFAs in some foods that are also sources of ω6.

An important systematic review, which evaluated prospective cohort studies and randomized controlled trials involving individuals in primary and secondary prevention, showed that ω6 intake was not associated with a lower risk of CAD, in contrast to what was observed for fish or marine ω3 intake.9393. Mente A, de Koning L, Shannon HS et al. A systematic review of the evidence supporting a causal link between dietary factors and coronary heart disease. Arch Intern Med. 2009; 169(7):659-69.In fact, several studies have shown a lower reduction in cardiovascular outcomes with the replacement of SFAs with ω6 than with combined ω6 and ω3.119119. Ramsden CE, Hibbeln JR, Majchrzak SF et al. n-6 fatty acid-specific and mixed polyunsaturate dietary interventions have different effects on CHD risk: a meta-analysis of randomised controlled trials. Br J Nutr. 2010; 104(11):1586-600.

The Cochrane Collaboration published a review of clinical trials evaluating the effect of ω6 intake on primary CVD prevention and concluded that the intake of ω6 fatty acids (linoleic, gamma-linolenic, dihomo-gamma-linolenic, and arachidonic acids) did not interfere with lipid or blood pressure markers; however, none of the studies assessed clinical outcomes.6565. Hooper L, Al-Khudairy L, Abdelhamid AS et al. Omega-6 fats for the primary and secondary prevention of cardiovascular disease. Cochrane Database Syst Rev. 2018 Nov;11:CD011094. , 120120. Al-Khudairy L, Hartley L, Clar C et al. Omega 6 fatty acids for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev. 2015 Nov; (11):CD011094. In a more recent review, also conducted by the Cochrane Collaboration, which evaluated the effect of ω6 supplementation on risk factors (blood pressure, lipid profile, and adiposity) and cardiovascular outcomes (all-cause mortality, CVD mortality, and cardiovascular events), little or no benefit was observed from ω6 interventions on all-cause mortality (RR = 1.0; 95% CI: 0.88-1.12), CVD mortality (RR = 1.09; 95% CI: 0.76-1.55), and cardiovascular events (RR = 0.97; 95% CI: 0.81-1.15).6565. Hooper L, Al-Khudairy L, Abdelhamid AS et al. Omega-6 fats for the primary and secondary prevention of cardiovascular disease. Cochrane Database Syst Rev. 2018 Nov;11:CD011094.Likewise, ω6 intake was not associated with a lower risk of cardiac and cerebrovascular events (RR = 0.84; 95% CI: 0.59-1.20) or stroke (RR = 1.36; 95% CI: 0.45-4.11). However, a slight reduction in the risk of acute myocardial infarction (AMI) was observed with increased ω6 intake (RR = 0.88; 95% CI: 0.76-1.02).6565. Hooper L, Al-Khudairy L, Abdelhamid AS et al. Omega-6 fats for the primary and secondary prevention of cardiovascular disease. Cochrane Database Syst Rev. 2018 Nov;11:CD011094.

Higher plasma concentration of ω6 was associated with lower risk of cardiovascular events, ischemic stroke, and CVD mortality, based on the results of a recent study analyzing data from 30 prospective studies, for a total of 68 659 participants enrolled.121121. Marklund M, Wu JHY, Imamura F et al; Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Fatty Acids and Outcomes Research Consortium (FORCE). Biomarkers of dietary omega-6 fatty acids and incident cardiovascular disease and mortality. Circulation. 2019; 139(21):2422-36.In this publication, the authors reinforce the cardiovascular benefits of ω6 intake.

5.5. Polyunsaturated Fatty Acids (Marine Omega-3)

EPA and DHA have been investigated for their potential to reduce cardiovascular risk. The mechanisms proposed for cardiovascular benefits include reduced inflammatory markers and platelet aggregation, improved endothelial function, reduced blood pressure, and reduced triglyceridemia.122122. Bosch Egert S, Stehle P. Impact of n-3 fatty acids on endothelial function: results from human interventions studies. Curr Opin Clin Nutr Metab Care. 2011; 14(2):121-31.

123. Flock MR, Skulas-Ray AC, Harris WS et al. Effects of supplemental long-chain omega-3 fatty acids and erythrocyte membrane fatty acid content on circulating inflammatory markers in a randomized controlled trial of healthy adults. Prostaglandins Leukot Essent Fatty Acids. 2014; 91(4):161-8.
- 124124. Ito MK. Long-chain omega-3 fatty acids, fibrates and niacin as therapeutic options in the treatment of hypertriglyceridemia: a review of the literature. Atherosclerosis. 2015; 242(2):647-56. Marine ω3 fatty acids (DHA and EPA) exert numerous effects on different physiological and metabolic processes, which can influence the likelihood of developing CVD.

Although initial evidence suggests a protective effect of the intake of fish and marine ω3 fatty acids on cardiovascular events, especially in people with established CVD,125125. Burr ML, Fehily AM, Gilbert JF et al. Effects of changes in fat, fish, and fibre intakes on death and myocardial reinfarction: diet and reinfarction trial (DART). Lancet. 1989; 2(8666):757-61.

126. GISSI-Prevenzione Investigators. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto miocardico. Lancet. 1999; 354(9177):447-55.
- 127127. Yokoyama M, Origasa H, Matsuzaki M et al.; Japan EPA lipid intervention study (JELIS) Investigators. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis. Lancet. 2007; 369(9567):1090-8. recent studies have not shown benefits of ω3 supplementation in people with previous manifestations of atherosclerotic disease.128128. Kromhout D, Giltay EJ, Geleijnse JM. Alpha Omega Trial Group. n-3 fatty acids and cardiovascular events after myocardial infarction. N Engl J Med. 2010; 363(21):2015-26.

129. Rauch B, Schiele R, Schneider S et al.; OMEGA Study Group. OMEGA, a randomized, placebo-controlled trial to test the effect of highly purified omega-3 fatty acids on top of modern guideline-adjusted therapy after myocardial infarction. Circulation. 2010; 122(21):2152-9.
- 130130. Galan P, Kesse-Guyot E, Czernichow S et al. SU.FOL.OM3 Collaborative Group. Effects of B vitamins and omega 3 fatty acids on cardiovascular diseases: a randomised placebo controlled trial. BMJ. 2010 Nov; 341:c6273. A possible explanation is related to the characteristics of the population studied, especially regarding the more frequent use of well-known protective agents (e.g., statins, beta-blockers, angiotensin-converting enzyme inhibitors), the more aggressive control of traditional risk factors, and the larger number of revascularization procedures in more recent studies. Therefore, it is questioned whether ω3 fatty acids can bring real additional benefits when patients are treated according to current recommendations. Questions regarding formulation, dose, and duration of supplementation may also be raised. In the Alpha Omega128128. Kromhout D, Giltay EJ, Geleijnse JM. Alpha Omega Trial Group. n-3 fatty acids and cardiovascular events after myocardial infarction. N Engl J Med. 2010; 363(21):2015-26.and SU.FOL.OM3 trials,130130. Galan P, Kesse-Guyot E, Czernichow S et al. SU.FOL.OM3 Collaborative Group. Effects of B vitamins and omega 3 fatty acids on cardiovascular diseases: a randomised placebo controlled trial. BMJ. 2010 Nov; 341:c6273.the dose of EPA+DHA (400 to 600 mg/day) may have been insufficient to produce a clinical benefit.

A recent meta-analysis of randomized controlled trials and prospective cohort studies evaluating the association between EPA+DHA intake and CAD risk showed a significant benefit only in populations at higher risk, including those with hypertriglyceridemia. The results of prospective cohort studies showed a significant reduction in the risk of any coronary event with higher intakes of EPA+DHA. Therefore, EPA+DHA intake appears to be associated with a reduced risk of coronary events, with greater benefit in populations at higher risk in randomized controlled studies.131131. Alexander DD, Miller PE, Van Elswyk ME et al. A meta-analysis of randomized controlled trials and prospective cohort studies of eicosapentaenoic and docosahexaenoic long-chain omega-3 fatty acids and coronary heart disease risk. Mayo Clin Proc. 2017; 92(1):15-29.

However, different formulations of ω3 and the populations studied seem to contribute to the results. Two recent controlled trials showed conflicting data, but there were differences in the dose and formulation of ω3 used. The ASCEND (A Study of Cardiovascular Events in Diabetes),132132. ASCEND Study Collaborative Group, Bowman L, Mafham M, Wallendszus K, Stevens W et al. Effects of n-3 fatty acid supplements in diabetes mellitus. N Engl J Med. 2018; 379(16):1540-50.which evaluated 15 840 patients with diabetes mellitus but without evidence of CVD, showed no significant differences between patients who consumed 1.0 g of EPA+DHA and those who received placebo. A review conducted by the Cochrane Collaboration, which included 79 clinical trials, for a total of 1 120 059 participants enrolled with a 12- to 72-month follow-up, showed that EPA, docosapentaenoic acid (DPA), and DHA had little or no effect on all-cause mortality (RR = 0.98; 95% CI: 0.90-1.03), CVD mortality (RR = 0.95; 95% CI: 0.87-1.03), and cardiovascular events (RR = 0.99; 95% CI: 0.94-1.04).133133. Abdelhamid AS, Brown TJ, Brainard JS, Biswas P, Thorpe GC, Moore HJ, et al. Omega-3 fatty acids for the primary and secondary prevention of cardiovascular disease. Cochrane Database of Syst Rev. 2018 Jul; (11):CD003177.

In the Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT),134134. Bhatt DL, Steg PG, Miller M et al; REDUCE-IT Investigators. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med. 2019; 380(1):11-22.involving high-risk patients with elevated TG levels receiving statin therapy, the risk of ischemic events, including CVD death, was significantly lower in patients who received 2 g of icosapent-ethyl ester twice daily (total daily dose of 4 g) than in those who received placebo. In a total sample of 8179 patients (70.7% enrolled for secondary prevention) followed for a median of 4.9 years, there was a 25% reduction in the risk of the primary composite endpoint (HR = 0.75; 95% CI: 0.68-0.83; P < 0.001), key secondary endpoint events (HR = 0.74; 95% CI: 0.65-0.83; P < 0.001), and prespecified events, including the rate of CVD death (HR = 0.80; 95% CI: 0.66-0.98; P = 0.03). However, a higher rate of patients in the EPA group were hospitalized for atrial fibrillation or flutter, with no differences in the risk of bleeding. It is worth noting that icosapent ethyl is not a fatty acid found in food, and its indication, in pharmacological doses, is made at the physician’s discretion.

Therefore, although there is a consensus that regular intake of fish rich in ω3 fatty acids should be part of a healthy diet, there is still no safe recommendation for supplementing fish-oil capsules. This occurs because the topic is still surrounded by controversy, fueled by conflicting results from clinical trials.

Using experimental models of atherosclerosis in mice, several studies have reported that fish oil and EPA can attenuate the atherosclerotic process, although the same has not been demonstrated in other experimental conditions.135135. Wang HH, Hung TM, Wei J et al. Fish oil increases antioxidant enzyme activities in macrophages and reduces atherosclerotic lesions in apoE-knockout mice. Cardiovasc Res. 2004;61(1):169-76.

136. Saraswathi V, Gao L, Morrow JD et al. Fish oil increases cholesterol storage in white adipose tissue with concomitant decreases in inflammation, hepatic steatosis, and atherosclerosis in mice. J Nutr. 2007; 137(7):1776-82.

137. Zampolli A, Bysted A, Leth T et al. Contrasting effect of fish oil supplementation on the development of atherosclerosis in murine models. Atherosclerosis. 2006;184(1):78-85.

138. Casós K, Sáiz MP, Ruiz-Sanz JI et al. Atherosclerosis prevention by a fish oil-rich diet in apoE(-/-) mice is associated with a reduction of endothelial adhesion molecules. Atherosclerosis. 2008; 201(2):306-17.

139. Matsumoto M, Sata M, Fukuda D et al. Orally administered eicosapentaenoic acid reduces and stabilizes atherosclerotic lesions in ApoE-deficient mice. Atherosclerosis. 2008; 197(2):524-33.
- 140140. Xu Z, Riediger N, Innis S et al. Fish oil significantly alters fatty acid profiles in various lipid fractions but not atherogenesis in apo E-KO mice. Eur J Nutr. 2007; 46(2):103-10. Some population-based studies suggest an inverse association between fish or marine ω3 fatty acid intake and subclinical atherosclerosis markers, such as carotid intima-media thickness and coronary calcification, although this relationship seems to be subtle.141141. Sekikawa A, Curb JD, Ueshima H et al.; ERA JUMP (Electron-beam tomography, risk factor assessment among japanese and u.s. men in the post-world war ii birth cohort) Study Group. Marine-derived n-3 fatty acids and atherosclerosis in Japanese, Japanese- American, and white men: a cross-sectional study. J Am Coll Cardiol. 2008; 52(6):417-24.

142. Heine-Bröring RC, Brouwer IA, Proença RV et al. Intake of fish and marine n-3 fatty acids in relation to coronary calcification: the Rotterdam Study. Am J Clin Nutr. 2010; 91(5):1317-23.
- 143143. He K, Liu K, Daviglus ML et al. Intakes of long-chain n-3 polyunsaturated fatty acids and fish in relation to measurements of subclinical atherosclerosis. Am J Clin Nutr. 2008; 88(4):1111-8. In a randomized trial of patients with CAD, supplementation with approximately 1.5 g/day of ω3 fatty acids for 2 years resulted in less progression and more regression of coronary atherosclerosis, as assessed by quantitative invasive angiography, compared to placebo, although the differences were small.144144. von Schacky C, Angerer P, Kothny W et al. The effect of dietary omega-3 fatty acids on coronary atherosclerosis: a randomized, double-blind, placebo-controlled trial. Ann Intern Med. 1999; 130(7):554-62.However, in another study, supplementation did not change the progression of carotid atherosclerosis, as assessed by ultrasound,145145. Angerer P, Kothny W, Störk S et al. Effect of dietary supplementation with omega-3 fatty acids on progression of atherosclerosis in carotid arteries. Cardiovasc Res. 2002;54(1):183-90which disagrees with the results of the randomized trial conducted by Mita et al.,146146. Mita T, Watada H, Ogihara T et al. Eicosapentaenoic acid reduces the progression of carotid intima-media thickness in patients with type 2 diabetes. Atherosclerosis. 2007; 191(1):162-7.who reported that highly purified EPA (1.8 g/day) attenuated the progression of carotid intima-media thickening in patients with diabetes.146146. Mita T, Watada H, Ogihara T et al. Eicosapentaenoic acid reduces the progression of carotid intima-media thickness in patients with type 2 diabetes. Atherosclerosis. 2007; 191(1):162-7.

It is also possible that ω3 fatty acids play a protective role against cardiovascular events by modulating atherosclerotic plaque characteristics, making the plaque more stable. A randomized trial of patients awaiting carotid endarterectomy showed that atherosclerotic plaques readily incorporated ω3 fatty acids from fish-oil supplementation, making them less vulnerable to rupture and instability phenomena,147147. Thies F, Garry JM, Yaqoob P et al. Association of n-3 polyunsaturated fatty acids with stability of atherosclerotic plaques: a randomised controlled trial. Lancet. 2003; 361(9356):477-85.an observation consistent with experimental findings.139139. Matsumoto M, Sata M, Fukuda D et al. Orally administered eicosapentaenoic acid reduces and stabilizes atherosclerotic lesions in ApoE-deficient mice. Atherosclerosis. 2008; 197(2):524-33.

5.5.1. Effects on Peripheral Vascular Disease

Despite extensive research on the effects of ω3 fatty acids on improving vascular function, their effects on cardiovascular outcomes in individuals with peripheral arterial disease are less described. A meta-analysis of 5 studies with a total of 396 participants, published between 1990 and 2010, was conducted to evaluate this issue.148148. Leng GC, Lee AJ, Fowkes FG et al. Randomized controlled trial of gamma-linolenic acid and eicosapentaenoic acid in peripheral arterial disease. Clin Nutr. 1998; 17(6):265-71.

149. Carrero JJ, Lopez-Huertas E, Salmeron LM et al. Daily supplementation with (n-3) PUFAs, oleic acid, folic acid, and vitamins B-6 and E increases pain-free walking distance and improves risk factors in men with peripheral vascular disease. J Nutr. 2005; 135(6):1393-99.

150. Carrero JJ, López-Huertas E, Salmerón LM et al. Simvastatin and supplementation with ω-3 polyunsaturated fatty acids and vitamins improves claudication distance in a randomized PILOT study in patients with peripheral vascular disease. Nutr Res. 2006; 26(12):637-43.

151. Gans RO, Bilo HJ, Weersink EG et al. Fish oil supplementation in patients with stable claudication. Am J Surg. 1990;160(5):490-5.
- 152152. Ishikawa Y, Yokoyama M, Saito Y et al. JELIS Investigators. Preventive effects of eicosapentaenoic acid on coronary artery disease in patients with peripheral artery disease. Circ J. 2010; 74(7):1451-7 In patients with peripheral vascular disease, there is insufficient evidence to recommend ω3 fatty acids for the reduction of major cardiovascular events, need for revascularization or amputation, improvement in pain-free walking distance, or improvement in quality of life.153153. Enns JE, Yeganeh A, Zarychanski R et al. The impact of omega-3 polyunsaturated fatty acid supplementation on the incidence of cardiovascular events and complications in peripheral arterial disease: a systematic review and meta-analysis. BMC Cardiovasc Disord. 2014 May; 14:70.

5.5.2. Effects on Cardiac Arrhythmia and Sudden Cardiac Death

Experimental studies have shown antiarrhythmic effects of ω3 fatty acids, mainly attributable to a direct effect on ion channels.154154. Saravanan P, Davidson NC, Schmidt EB et al. Cardiovascular effects of marine omega-3 fatty acids. Lancet. 2010; 376(9740):540-50.Other mechanisms include modulation of the autonomic tone (improved heart rate variability), reduction in basal heart rate, and restriction of reperfusion-induced arrhythmias.154154. Saravanan P, Davidson NC, Schmidt EB et al. Cardiovascular effects of marine omega-3 fatty acids. Lancet. 2010; 376(9740):540-50.These effects may explain the beneficial results of ω3 fatty acids in the prevention of sudden cardiac death reported in some studies.

Several observational studies have suggested that ω3 fatty acids can provide particular protection against sudden cardiac death, especially in patients with AMI. This beneficial effect was also observed in a subanalysis of the GISSI-Prevenzione randomized trial,155155. Marchioli R, Barzi F, Bomba E et al. GISSI-Prevenzione Investigators. Early protection against sudden death by n-3 polyunsaturated fatty acids after myocardial infarction: time-course analysis of the results of the Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico (GISSI)-Prevenzione. Circulation. 2002; 105(16):1897-903.but not in the most recent randomized trial, OMEGA.129129. Rauch B, Schiele R, Schneider S et al.; OMEGA Study Group. OMEGA, a randomized, placebo-controlled trial to test the effect of highly purified omega-3 fatty acids on top of modern guideline-adjusted therapy after myocardial infarction. Circulation. 2010; 122(21):2152-9.This hypothesis was also confirmed in patients with implantable cardioverter defibrillators. The results were inconsistent, ranging from a slight beneficial effect of ω3 fatty acids on the reduction of severe ventricular arrhythmias in this subset of patients156156. Leaf A, Albert CM, Josephson M et al. Fatty Acid Antiarrhythmia Trial Investigators. Prevention of fatal arrhythmias in high-risk subjects by fish oil n-3 fatty acid intake. Circulation. 2005; 112(18):2762-8.to a proarrhythmic effect in some patients.157157. Raitt MH, Connor WE, Morris C et al. Fish oil supplementation and risk of ventricular tachycardia and ventricular fibrillation in patients with implantable defibrillators: a randomized controlled trial. JAMA. 2005; 293(23):2884-91.

Due to conflicting results, data from a meta-analysis were evaluated, for a total of 32 919 participants included in 9 studies. Of these, 16 465 patients received ω3 and 16 454 received placebo. There was a non-significant reduction in the risk of sudden cardiac death or ventricular arrhythmias with the use of ω3 fatty acids (OR = 0.82; 95% CI: 0.60-1.21; P = 0.21).158158. Khoueiry G, Rafeh NA, Sullivan E et al. Do omega-3 polyunsaturated fatty acids reduce risk of sudden cardiac death and ventricular arrhythmias? A meta-analysis of randomized trials. Heart Lung. 2013; 42(4):251-6.

Another review evaluated the results of studies using ω3 fatty acids in ventricular arrhythmias and sudden cardiac death, questioning whether these lipids produce antiarrhythmic, proarrhythmic, or neutral effects, which, in turn, would require randomized controlled trials with a specific design for these populations.159159. Albert CM. Omega-3 fatty acids, ventricular arrhythmias, and sudden cardiac death: antiarrhythmic, proarrhythmic, or neither. Circ Arrhythm Electrophysiol. 2012; 5(3):456-9.

5.5.3. Effects on Heart Failure

A large randomized controlled trial, the GISSI-HF trial, showed a slight reduction in mortality when ω3 (1 g/day) was supplemented in patients with New York Heart Association (NYHA) class II-IV heart failure (HF),160160. Gissi-HF Investigators, Tavazzi L, Maggioni AP et al. Effect of n-3 polyunsaturated fatty acids in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet. 2008; 372(9645):1223-30.which is consistent with other epidemiological and observational studies that suggested an inverse relationship between fish or ω3 intake and HF-related events.161161. Mozaffarian D, Bryson CL, Lemaitre RN et al. Fish intake and risk of incident heart failure. J Am Coll Cardiol. 2005; 45(12):2015-21. , 162162. Yamagishi K, Iso H, Date C et al. Japan Collaborative Cohort Study for Evaluation of Cancer Risk Study Group. Fish, omega-3 polyunsaturated fatty acids, and mortality from cardiovascular diseases in a nationwide community-based cohort of Japanese men and women the JACC (Japan Collaborative Cohort Study for Evaluation of Cancer Risk) Study. J Am Coll Cardiol. 2008; 52(12):988-96.

Recommendations from national and international guidelines consider ω3 supplementation in HF a class IIb indication (level of evidence B) based on data from the GISSI-HF trial,160160. Gissi-HF Investigators, Tavazzi L, Maggioni AP et al. Effect of n-3 polyunsaturated fatty acids in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet. 2008; 372(9645):1223-30.but not from other studies in which ω3 fatty acids have been supplemented.

In the GISSI-HF trial, which included 6975 patients with NYHA class II-IV HF or an ejection fraction <40% or who had been hospitalized in the preceding year for HF, 1 g of ω3 was added to standard therapy. This therapy included angiotensin-converting enzyme inhibitors/angiotensin receptor blockers in 94% of patients, beta blockers in 65%, and spironolactone in 39%. Patients were followed for a median of 3.9 years. Supplementation with ω3 fatty acids reduced by 8% the co-primary endpoint of CVD death or hospitalization: 10% in the relative risk of CVD death and 7% in cardiovascular hospitalizations.160160. Gissi-HF Investigators, Tavazzi L, Maggioni AP et al. Effect of n-3 polyunsaturated fatty acids in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet. 2008; 372(9645):1223-30.

5.6. Polyunsaturated Fatty Acids (Vegetable Omega-3)

Although the real impact of vegetable-derived ω3 fatty acids on CVD is still under debate, most prospective observational studies suggest that ALA intake may protect against cardiovascular events.163163. Mozaffarian D. Does alpha-linolenic acid intake reduce the risk of coronary heart disease? A review of the evidence. Altern Ther Health Med. 2005; 11(3):24-30.In the HPFS study, the prospective analysis of more than 45 000 men showed that ω3 intake, both of marine and vegetable origin, was associated with a reduction in cardiovascular risk, with little influence of ω6 intake.164164. Mozaffarian D, Ascherio A, Hu FB et al. Interplay between different polyunsaturated fatty acids and risk of coronary heart disease in men. Circulation. 2005; 111(2):157-164.In the NHS study, which assessed cardiovascular outcomes in more than 76 000 women, ALA intake was inversely associated with the risk of sudden cardiac death, but not with other types of fatal coronary outcomes or non-fatal AMI.165165. Albert CM, Oh K, Whang W et al. Dietary alpha-linolenic acid intake and risk of sudden cardiac death and coronary heart disease. Circulation. 2005; 112(21):3232-8.

Meta-analyses and systematic reviews have produced conflicting results.9393. Mente A, de Koning L, Shannon HS et al. A systematic review of the evidence supporting a causal link between dietary factors and coronary heart disease. Arch Intern Med. 2009; 169(7):659-69. , 166166. Wang C, Harris WS, Chung M et al. n-3 Fatty acids from fish or fish-oil supplements, but not alpha-linolenic acid, benefit cardiovascular disease outcomes in primary- and secondary- prevention studies: a systematic review. Am J Clin Nutr. 2006; 84(1):5-17. , 167167. Brouwer IA, Katan MB, Zock PL. Dietary alpha-linolenic acid is associated with reduced risk of fatal coronary heart disease, but increased prostate cancer risk: a meta-analysis. J Nutr. 2004; 134(4):919-22. In the Alpha Omega randomized controlled trial, intake of a margarine supplemented with ALA for 40 months did not reduce the rate of cardiovascular events in patients who had had an AMI.128128. Kromhout D, Giltay EJ, Geleijnse JM. Alpha Omega Trial Group. n-3 fatty acids and cardiovascular events after myocardial infarction. N Engl J Med. 2010; 363(21):2015-26.As for the effectiveness of ALA, there was a slight reduction in the risk of cardiovascular events (RR = 0.95; 95% CI: 0.83-1.07), CVD mortality (RR = 0.95; 95% CI: 0.72-1.26), and arrhythmias (RR = 0.79; 95% CI: 0.57-1.10).133133. Abdelhamid AS, Brown TJ, Brainard JS, Biswas P, Thorpe GC, Moore HJ, et al. Omega-3 fatty acids for the primary and secondary prevention of cardiovascular disease. Cochrane Database of Syst Rev. 2018 Jul; (11):CD003177.

The role of the dietary ω6/ω3 ratio in the pathogenesis of cardiovascular, inflammatory, and autoimmune diseases has also been the subject of controversy in recent years. Humans have experienced dramatic changes in their diet regarding fatty acid intake in the last millennia. With the agricultural and industrial revolutions, there was an increase in the intake of cereals, oils, and grains rich in ω6, while the intake of ω3 decreased. The ω6/ω3 ratio, originally from 1:1 to 3:1, currently ranges from 15:1 to 40:1 in the Western diet.168168. Simopoulos AP. The importance of the ratio of omega-6/ omega-3 essential fatty acids. Biomed Pharmacother. 2002; 56(8):365-79. , 169169. Simopoulos AP. Evolutionary aspects of diet, the omega-6/ omega-3 ratio and genetic variation: nutritional implications for chronic diseases. Biomed Pharmacother. 2006; 60(9):502-7.

Most studies have concluded that, for general health promotion, the ω6/ω3 ratio should be lower than that currently observed in the general Western population.170170. Gómez Candela C, Bermejo López LM, Loria Kohen V. Importance of a balanced omega 6/omega 3 ratio for the maintenance of health: nutritional recommendations. Nutr Hosp. 2011; 26(2):323-9.Some experts advocate for a reduction in this ratio both by increasing ω3 intake and by reducing ω6 intake. Accordingly, in a prospective randomized secondary prevention trial of post-AMI patients, an experimental Mediterranean diet characterized, among other factors, by being richer in ALA (C18:3 – ω3) and oleic acid (C18:1 – ω9) and poorer in linoleic acid (C18:2 – ω6) was associated with a reduction of up to 70% in overall mortality.171171. de Lorgeril M, Renaud S, Mamelle N et al. Mediterranean alpha-linolenic acid-rich diet in secondary prevention of coronary heart disease. Lancet. 1994; 343(8911):1454-9.The diet included the replacement of corn oil with olive oil, with a consequent decrease in the ω6/ω3 ratio to up to 4:1.171171. de Lorgeril M, Renaud S, Mamelle N et al. Mediterranean alpha-linolenic acid-rich diet in secondary prevention of coronary heart disease. Lancet. 1994; 343(8911):1454-9.

The evidence so far suggests that increased intake of ω3, particularly DHA and EPA, provides protection against CVD. In addition, several experts have questioned the validity of using the ω6/ω3 ratio alone in clinical practice and its relationship with cardiovascular risk.172172. Harris WS. The omega-6/omega-3 ratio and cardiovascular disease risk: uses and abuses. Curr Atheroscler Rep. 2006; 8(6):453-9. , 173173. Griffin BA. How relevant is the ratio of dietary n-6 to n-3 polyunsaturated fatty acids to cardiovascular disease risk? Evidence from the OPTILIP study. Curr Opin Lipidol. 2008; 19(1):57-62 Both fatty acids, ω6 and ω3, have been associated with beneficial effects on cardiovascular health. However, the importance of the ω6/ω3 ratio is based on the enzymatic competition between ω6 and ω3 due to the action of delta-6 desaturase, which converts both into different subspecies. On the one hand, high ω6 intake can decrease the metabolism of ω3 (ALA – C18:3) to EPA (C20:5) and DHA (C22:6),174174. Liou YA, King DJ, Zibrik D et al. Decreasing linoleic acid with constant alpha-linolenic acid in dietary fats increases (n-3) eicosapentaenoic acid in plasma phospholipids in healthy men. J Nutr. 2007; 137(4):945-52.thus limiting the benefits of ω3 fatty acids. On the other hand, the higher affinity of delta-6 desaturase for ω3 fatty acids may lead the essential metabolites derived from the bioconversion of ω6 not to be produced satisfactorily, which would support a recommendation for a small increase in its intake compared to ω3.172172. Harris WS. The omega-6/omega-3 ratio and cardiovascular disease risk: uses and abuses. Curr Atheroscler Rep. 2006; 8(6):453-9.

In view of these issues and until further scientific evidence is available to support changes in current approaches, dietary recommendations should be based on the total intake of each fatty acid type (ω6 and ω3), and not only on the ω6/ω3 ratio.

5.7. Trans Fats

Several observational studies have associated the intake of trans fatty acids, or foods containing trans fats, with adverse cardiovascular outcomes.7676. Mozaffarian D, Katan MB, Ascherio A et al. Trans fatty acids and cardiovascular disease. N Engl J Med. 2006; 354(15):1601. , 175175. Hu FB, Stampfer MJ, Manson JE et al. Dietary fat intake and the risk of coronary heart disease in women. N Engl J Med. 1997; 337(21):1491.

176. Willett WC, Stampfer MJ, Manson JE et al. Intake of trans fatty acids and risk of coronary heart disease among women. Lancet. 1993; 341(8845):581.

177. Gillman MW, Cupples LA, Gagnon D et al. Margarine intake and subsequent coronary heart disease in men. Epidemiology. 1997; 8(2):144-9.

178. Oomen CM, Ocké MC, Feskens EJ et al. Association between trans fatty acid intake and 10-year risk of coronary heart disease in the Zutphen Elderly Study: a prospective population-based study. Lancet. 2001; 357(9258):746-51.

179. Guasch-Ferré M, Babio N, Martínez-González MA et al. Dietary fat intake and risk of cardiovascular disease and all-cause mortality in a population at high risk of cardiovascular disease. Am J Clin Nutr. 2015; 102(6):1563-73.
- 180180. Wang DD, Li Y, Chiuve SE et al. Association of Specific Dietary Fats With Total and Cause-Specific Mortality. JAMA Intern Med. 2016; 176(8):1134-45. An analysis of data from the NHS study showed that, for every 2% increase in trans fat intake, there was a 1.93-fold increase in the relative risk of coronary heart disease.175175. Hu FB, Stampfer MJ, Manson JE et al. Dietary fat intake and the risk of coronary heart disease in women. N Engl J Med. 1997; 337(21):1491.Likewise, the replacement of 2% energy from trans fats with UFAs reduced cardiovascular risk by 53%, as shown in the Seven Countries Study population.181181. Menotti A, Kromhout D, Blackburn H et al. Food intake patterns and 25-year mortality from coronary heart disease: cross cultural correlations in the Seven Countries Study. The Seven Countries Study Research Group. Eur J Epidemiol. 1999; 15(6):507-15.

The Cardiovascular Health Study (CHS)182182. Wang Q, Imamura F, Lemaitre RN et al. Plasma phospholipid trans-fatty acids levels, cardiovascular diseases, and total mortality: the cardiovascular health study. J Am Heart Assoc. 2014; 3(4). pii: e000914.evaluated the plasma concentration of trans fatty acids (elaidic acid) in 2742 adults and showed that these fatty acids were associated with an increase in total mortality, mainly due to increased cardiovascular risk. A study evaluating the NHS and HPFS studies’ databases also showed that trans fat intake increased total mortality to 13%, when comparing the highest to the lowest quintile of intake.180180. Wang DD, Li Y, Chiuve SE et al. Association of Specific Dietary Fats With Total and Cause-Specific Mortality. JAMA Intern Med. 2016; 176(8):1134-45.

This deleterious effect of trans fats on cardiovascular risk may be attributable to its action on increasing LDLc and decreasing ATP binding cassette transporters A1 (ABCA1) and G1 (ABCG1), responsible for cholesterol efflux from macrophages to ApoA-I and HDL, respectively.183183. Fournier N, Attia N, Rousseau-Ralliard D et al. Deleterious impact of elaidic fatty acid on ABCA1-mediated cholesterol efflux from mouse and human macrophages. Biochim Biophys Acta. 2012; 1821(2):303-12.

6. Endothelial Dysfunction

Endothelial dysfunction is one of the initial events in the genesis of CVD and results mainly from reduced production and/or availability of nitric oxide (NO) and from an imbalance between endothelium-derived vasodilator and vasoconstrictor factors.184184. Godo S, Shimokawa H. Endothelial functions. Arterioscler Thromb Vasc Biol. 2017; 37(9):e108-14. , 185185. Ghosh A, Gao L, Thakur A et al. Role of free fatty acids in endothelial dysfunction. J Biomed Sci. 2017;24(1):50. Cardiovascular risk factors, such as oxidized LDL, dyslipidemia, hypertension, hyperglycemia, hyperinsulinemia, and smoking, can induce endothelial activation, which induces increased production of cytokines, chemokines, and reactive oxygen species (ROS), thus reducing the capacity for NO-dependent vasodilation. In addition, there is an increase in endothelial permeability, which facilitates the transport of LDL to the subendothelial layer, where LDL can undergo modifications (by oxidation or glycation) and trigger an inflammatory response. This can lead endothelial cells to express cell adhesion molecules and produce mediators that will promote chemotaxis of inflammatory cells, platelet activation, and smooth muscle cell (SMC) proliferation and migration, thus contributing to the genesis of atherosclerosis.186186. Mundi S, Massaro M, Scoditti E et al. Endothelial permeability, LDL deposition, and cardiovascular risk factors-a review. Cardiovasc Res. 2018; 114(1):35-52. , 187187. Geovanini GR, Libby P. Atherosclerosis and inflammation: overview and updates. Clin Sci. 2018; 132(12):1243-52. NO, on the other hand, is able to reduce the expression of inflammatory mediators and endothelial cell adhesion molecules and to decrease vascular reactivity, thus preventing vasoconstriction at the injury site.188188. Gori T. Endothelial Function: A Short Guide for the Interventional Cardiologist. Int J Mol Sci. 2018; 19(12). pii: E3838. , 189189. Hadi HA, Carr CS, Al Suwaidi J. Endothelial dysfunction: cardiovascular risk factors, therapy, and outcome. Vasc Health Risk Manag. 2005;1(3):183-98.

A high-fat diet has been shown to reduce the activation of the endothelial AMPK-PI3K-Akt-eNOS pathway, leading to endothelial dysfunction.185185. Ghosh A, Gao L, Thakur A et al. Role of free fatty acids in endothelial dysfunction. J Biomed Sci. 2017;24(1):50. , 190190. Nakamura K, Miyoshi T, Yunoki K et al. Postprandial hyperlipidemia as a potential residual risk factor. J Cardiol. 2016; 67(4):335-9. , 191191. Newens KJ, Thompson AK, Jackson KG et al. Endothelial function and insulin sensitivity during acute non-esterified fatty acid elevation: Effects of fat composition and gender. Nutr Metab Cardiovasc Dis. 2015; 25(6):575-81. In experimental animals, consumption of a high-fat diet for 6 weeks increased the plasma concentration of pro-inflammatory cytokines and reduced adiponectin concentrations, while reducing NO production and promoting endothelial dysfunction.192192. Oishi JC, Castro CA, Silva KA et al. Endothelial dysfunction and inflammation precedes elevations in blood pressure induced by a high-fat diet. Arq Bras Cardiol. 2018; 110(6):558-67.

SFAs, especially palmitic acid, activate inflammatory responses and oxidative stress, which impair endothelial integrity and cause endothelial dysfunction. SFAs are able to activate the transcription nuclear factor kappa B (NF-κB), which controls inflammatory signaling and oxidative stress pathways,193193. Ishiyama J, Taguchi R, Akasaka Y et al. Unsaturated FAs prevent palmitate-induced LOX-1 induction via inhibition of ER stress in macrophages. J Lipid Res. 2011; 52(2):299-307.and, consequently, induce endothelial dysfunction by increasing ROS and secreting pro-inflammatory cytokines, such as interleukin (IL)-6 and tumor necrosis factor (TNF)-α.194194. Lee CH, Lee SD, Ou HC et al. Eicosapentaenoic acid protects against palmitic acid-induced endothelial dysfunction via activation of the AMPK/eNOS pathway. Int J Mol Sci. 2014; 15(6):10334-49. , 195195. Wen H, Gris D, Lei Y et al. Fatty acid-induced NLRP3-ASC inflammasome activation interferes with insulin signaling. Nat Immunol. 2011; 12(5):408-15.

In a study on endothelial cells, palmitic acid inhibited insulin-dependent activation of endothelial NO synthase (eNOS), thereby reducing NO production, an effect mediated by the activation of PTEN (phosphatase and tensin homolog deleted on chromosome 10). Such phosphatase, when activated, reduces protein kinase B (Akt) phosphorylation.196196. Wang XL, Zhang L, Youker K et al. Free fatty acids inhibit insulin signaling-stimulated endothelial nitric oxide synthase activation through upregulating PTEN or inhibiting Akt kinase. Diabetes. 2006; 55(8):2301-10.In another study, treatment of endothelial cells with palmitic acid decreased NO production by reducing insulin-mediated phosphorylation of insulin receptor substrate-1 (IRS-1), Akt, and eNOS. This effect was dependent on increased palmitic acid-mediated IκB kinase (IKK)-β activation.197197. Kim F, Tysseling KA, Rice J et al. Free fatty acid impairment of nitric oxide production in endothelial cells is mediated by IKKbeta. Arterioscler Thromb Vasc Biol. 2005; 25(5):989-94.

SFAs can promote inflammation and endoplasmic reticulum (ER) stress in different cell types.6969. Ishida T, Ohta M, Nakakuki M et al. Distinct regulation of plasma LDL cholesterol by eicosapentaenoic acid and docosahexaenoic acid in high fat diet-fed hamsters: participation of cholesterol ester transfer protein and LDL receptor. Prostaglandins Leukot Essent Fatty Acids. 2013; 88(4):281-8 , 193193. Ishiyama J, Taguchi R, Akasaka Y et al. Unsaturated FAs prevent palmitate-induced LOX-1 induction via inhibition of ER stress in macrophages. J Lipid Res. 2011; 52(2):299-307. , 194194. Lee CH, Lee SD, Ou HC et al. Eicosapentaenoic acid protects against palmitic acid-induced endothelial dysfunction via activation of the AMPK/eNOS pathway. Int J Mol Sci. 2014; 15(6):10334-49. , 198198. Sokolova M, Vinge LE, Alfsnes K et al. Palmitate promotes inflammatory responses and cellular senescence in cardiac fibroblasts. Biochim Biophys Acta. 2017; 1862(2):234-45. , 199199. Zhang Y, Xia G, Zhang Y et al. Palmitate induces VSMC apoptosis via toll like receptor (TLR)4/ROS/p53 pathway. Atherosclerosis. 2017 Aug; 263:74-81. In cardiac fibroblasts, palmitic acid activated inflammatory pathways and induced mitochondrial dysfunction and ER stress, leading to increased ROS production and inflammasome activation, an effect that was mitigated by the presence of EPA.198198. Sokolova M, Vinge LE, Alfsnes K et al. Palmitate promotes inflammatory responses and cellular senescence in cardiac fibroblasts. Biochim Biophys Acta. 2017; 1862(2):234-45.In SMCs, palmitic acid is able to induce apoptosis through toll-like receptor 4 (TLR4) activation, increased ROS production, and increased caspase 3 and caspase 9 expression.199199. Zhang Y, Xia G, Zhang Y et al. Palmitate induces VSMC apoptosis via toll like receptor (TLR)4/ROS/p53 pathway. Atherosclerosis. 2017 Aug; 263:74-81.In macrophages, SFAs increase the content of oxidized LDL receptor-1 (LOX-1) with a subsequent increase in the uptake of oxidized LDL, leading to increased ROS production and ER stress, effects that were corrected by adding UFAs to the medium.193193. Ishiyama J, Taguchi R, Akasaka Y et al. Unsaturated FAs prevent palmitate-induced LOX-1 induction via inhibition of ER stress in macrophages. J Lipid Res. 2011; 52(2):299-307.In endothelial cells, treatment with palmitic acid induced endothelial dysfunction and reduced eNOS and AMPK phosphorylation, with a subsequent reduction in NO production. Also, palmitic acid induced increases in ROS, inducible nitric oxide synthase (iNOS), and apoptosis, actions that were attenuated by concomitant incubation with EPA.194194. Lee CH, Lee SD, Ou HC et al. Eicosapentaenoic acid protects against palmitic acid-induced endothelial dysfunction via activation of the AMPK/eNOS pathway. Int J Mol Sci. 2014; 15(6):10334-49..

Habitual consumption of an SFA-rich diet was associated with changes in endothelial function in overweight young adults.200200. Lambert EA, Phillips S, Belski R et al. Endothelial function in healthy young individuals is associated with dietary consumption of saturated fat. Front Physiol. 2017 Nov; 8:876.However, intervention studies assessing the effect of acute SFA intake on endothelial function have produced controversial results. The Dietary Intervention and VAScular function (DIVAS) study, involving adults with moderate cardiovascular risk, reported that 16-week isocaloric replacement of SFAs with MUFAs or linoleic acid had no effect on endothelial function, inflammatory markers, or insulin resistance. However, there was a reduction in the plasma concentrations of TC, LDLc, and E-selectin.201201. Vafeiadou K, Weech M, Altowaijri H et al. Replacement of saturated with unsaturated fats had no impact on vascular function but beneficial effects on lipid biomarkers, E-selectin, and blood pressure: results from the randomized, controlled Dietary Intervention and VAScular function (DIVAS) study. Am J Clin Nutr. 2015; 102(1):40-8.The DIVAS-2 study, which evaluated the acute effect of high-fat meals on endothelial function and cardiovascular risk markers in postmenopausal women, found no difference in the impact of different fatty acids on markers of endothelial function.202202 Rathnayake KM, Weech M, Jackson KG et al. Meal fatty acids have differential effects on postprandial blood pressure and biomarkers of endothelial function but not vascular reactivity in postmenopausal women in the randomized controlled dietary intervention and vascular function (DIVAS)-2 Study. J Nutr. 2018; 148(3):348-57.

SFAs, especially palmitic acid, activate inflammatory responses and oxidative stress, which impair endothelial integrity and cause endothelial dysfunction. Fish-oil supplementation significantly improved endothelial function in forearm resistance vessels.123123. Flock MR, Skulas-Ray AC, Harris WS et al. Effects of supplemental long-chain omega-3 fatty acids and erythrocyte membrane fatty acid content on circulating inflammatory markers in a randomized controlled trial of healthy adults. Prostaglandins Leukot Essent Fatty Acids. 2014; 91(4):161-8.Compared to placebo, systemic vascular compliance improved after 3 g/day of DHA or EPA for 7 weeks.203203. Nestel P, Shige H, Pomeroy S et al. The n-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid increase systemic arterial compliance in humans. Am J Clin Nutr. 2002; 76(2):326-30.The proposed mechanisms include the incorporation of ω3 into membrane phospholipids, thus changing vascular compliance.6868. Harris WS, Miller M, Tighe AP et al. Omega-3 fatty acids and coronary heart disease risk: clinical and mechanistic perspectives. Atherosclerosis 2008;197(1):12-24Attenuation of age-related vascular stiffness in patients with dyslipidemia and carotid artery distensibility is another proposed mechanism.204204. Tomiyama H, Takazawa K, Osa S et al. Do eicosapentaenoic acid supplements attenuate age-related in- creases in arterial stiffness in patients with dyslipidemia? A preliminary study. Hypertens Res. 2005; 28(8):651-5.Endothelial dysfunction is closely associated with vascular wall inflammation. The effects of marine ω3 supplementation on in vivo endothelial function in humans are still controversial. An analysis of 33 intervention trials suggests that marine ω3 fatty acids may improve endothelial function in overweight dyslipidemic patients and in patients with diabetes, although the results are conflicting in patients with CVD and inconsistent in healthy individuals.6363. Egert S, Kratz M, Kannenberg F et al. Effects of high-fat and low-fat diets rich in monounsaturated fatty acids on serum lipids, LDL size and indices of lipid peroxidation in healthy non-obese men and women when consumed under controlled conditions. Eur J Nutr. 2011; 50(1):71-9.

A study of endothelial cells showed that elaidic acid can cause cell death by activating the caspase pathway,205205. Zapolska-Downar D, Kosmider A, Naruszewicz M. Trans fatty acids induce apoptosis in human endothelial cells. J Physiol Pharmacol 2005; 56(6):611-25.as well as NF-κB activation by increasing ROS production, resulting in increased vascular cell and intercellular adhesion molecule (VCAM-1 and ICAM-1) expression and greater leukocyte adhesion.206206. Bryk D, Zapolska-Downar D, Malecki M et al. Trans fatty acids induce a proinflammatory response in endothelial cells through ROS-dependent nuclear factor-KB activation. J Physiol Pharmacol. 2011; 62(2):229-38.Consistent with these results, a study in humans reported an increase in plasma concentrations of E-selectin and C-reactive protein (CRP) with trans fat intake.207207. Baer DJ, Judd JT, Clevidence BA et al. Dietary fatty acids affect plasma markers of inflammation in healthy men fed controlled diets: a randomized crossover study. Am J Clin Nutr. 2004;79(6):969-73.Increased trans fat intake was also shown to increase the plasma concentrations of E-selectin, VCAM, and ICAM in 730 women who participated in the NHS study.208208. Lopez-Garcia E, Schulze MB, Meigs JB et al. Consumption of trans fatty acids is related to plasma biomarkers of inflammation and endothelial dysfunction. J Nutr. 2005; 135(3):562-6.A study on endothelial cells investigating the effect of trans fatty acids on NF-κB activation showed that elaidic acid induced IκB phosphorylation, as assessed by an increase in IL-6 concentrations.209209. Iwata NG, Pham M, Rizzo NO et al. Trans fatty acids induce vascular inflammation and reduce vascular nitric oxide production in endothelial cells. PLoS One. 2011; 6(12):e29600.It also led to a decrease in both NO production and insulin signaling, and promoted pro-inflammatory signaling and cell death.210210. Hirata Y, Takahashi M, Kudoh Y et al. Trans-Fatty acids promote proinflammatory signaling and cell death by stimulating the apoptosis signal-regulating kinase 1 (ASK1)-p38 pathway. J Biol Chem. 2017; 292(12):8174-85.

6.1. Blood Pressure

In dietary intervention studies in overweight patients, those consuming a daily fish meal showed a decrease in systolic and diastolic blood pressure, and this reduction was even greater when combined with a weight loss program, even after adjustment for other covariates.211211. Bao DQ, Mori T, Burke V et al. Effects of dietary fish and weight reduction on ambulatory blood pressure in over- weight hypertensives. Hypertension. 1998; 32(4):710-7.A meta-analysis conducted in the 1990s concluded that the effect of ω3 supplementation on blood pressure is dose-dependent, being effective from a dose of 3.0 g/day, with a reduction of 0.66 and 0.35 mm Hg in systolic and diastolic blood pressure, respectively, per gram of ω3 consumed.212212. Morris MC, Sacks F, Rosner B. Does fish oil lower blood pressure? A meta-analysis of controlled trials. Circulation. 1993; 88(2):523-33.

In another meta-analysis of 36 randomized trials, fish-oil supplementation (median dose of 3.7 g/day) reduced systolic blood pressure by 2.1 mm Hg and diastolic blood pressure by 1.6 mm Hg.213213. Geleijnse JM, Giltay EJ, Grobbee DE et al. Blood pressure response to fish oil supplementation: metaregression analysis of randomized trials. J Hypertens. 2002; 20(8):1493-9.These modest results can be explained by the low degree of purity and low concentrations in the formulations used. Other studies using low doses (1.6 g of DHA and 0.6 g of EPA) have not shown benefits in blood pressure, possibly because of the low doses used. In high-risk patients, such as those on hemodialysis, 4-month supplementation with 2 g of ω3 was associated with lower systolic (−9 mm Hg) and diastolic (−11 mm Hg) blood pressure, compared to olive oil.214214. Vernaglione L, Cristofano C, Chimienti S. Omega-3 polyunsaturated fatty acids and proxies of cardiovascular disease in hemodialysis: a prospective cohort study. J Nephrol. 2008; 21(1):99-105.

In a meta-analysis involving patients with T2D, ω3 supplementation reduced diastolic pressure by 1.8 mm Hg.215215. Hartweg J, Farmer AJ, Holman RR et al. Meta-analysis of the effects of n-3 polyunsaturated fatty acids on haematological and thrombogenic factors in type 2 diabetes. Diabetologia. 2007;50(2):250-8.Theobald et al.216216. Theobald HE, Goodall AH, Sattar N et al. Low-dose docosahexaenoic acid lowers diastolic blood pressure in middle-aged men and women. J Nutr. 2007; 137(4):973-8.also showed a reduction in blood pressure with the consumption of low doses of ω3.216216. Theobald HE, Goodall AH, Sattar N et al. Low-dose docosahexaenoic acid lowers diastolic blood pressure in middle-aged men and women. J Nutr. 2007; 137(4):973-8.However, when endothelial function or arterial stiffness rates are assessed, data are conflicting between studies.216216. Theobald HE, Goodall AH, Sattar N et al. Low-dose docosahexaenoic acid lowers diastolic blood pressure in middle-aged men and women. J Nutr. 2007; 137(4):973-8. , 217217. Hall WL, Sanders KA, Sanders TA et al. A high-fat meal enriched with eicosapentaenoic acid reduces postprandial arterial stiffness measured by digital volume pulse analysis in healthy men. J Nutr. 2008; 138(2):287-91.

Schwingshackl et al.218218. Schwingshackl L, Strasser B, Hoffmann G. Effects of monounsaturated fatty acids on cardiovascular risk factors: a systematic review and meta-analysis. Ann Nutr Metab. 2011; 59(2-4):176-86.conducted a systematic review and meta-analysis to investigate the impact of MUFAs on lipid metabolism, blood pressure, and cardiovascular events. The results showed that diets with MUFA content above 12% of energy had a beneficial effect only on diastolic and systolic blood pressure.

In addition to the benefits observed in the lipid profile,219219. Maki KC, Hasse W, Dicklin MR et al. Corn oil lowers plasma cholesterol compared with coconut oil in adults with above-desirable levels of cholesterol in a randomized crossover trial. J Nutr. 2018; 148(10):1556-63.the Mediterranean dietary pattern also improves blood pressure220220. Storniolo CE, Casillas R, Bulló M et al. A Mediterranean diet supplemented with extra virgin olive oil or nuts improves endothelial markers involved in blood pressure control in hypertensive women. Eur J Nutr. 2017; 56(1):89-97.and provides additional protection against oxidative stress,221221. Carnevale R, Pignatelli P, Nocella C et al. Extra virgin olive oil blunt post-prandial oxidative stress via nox2 down-regulation. Atherosclerosis. 2014; 235(2):649-58.inflammatory markers,222222. Rallidis LS, Kolomvotsou A, Lekakis J et al. Short-term effects of Mediterranean-type diet intervention on soluble cellular adhesion molecules in subjects with abdominal obesity. Clin Nutr ESPEN. 2017 Feb; 17:38-43.and endothelial dysfunction.112112. Casas R, Urpi-Sardà M, Sacanella E et al. anti-inflammatory effects of the Mediterranean diet in the early and late stages of atheroma plaque development. Mediators Inflamm. 2017 Apr; 2017:3674390.In this respect, it is noted that additional health benefits were conferred by other substances, independently of MUFAs. For such substances, there is currently no specific recommended intake.

Therefore, there is little evidence of the protective role of MUFAs against hypertension and endothelial dysfunction that could support specific recommendations.

6.2. Stroke

Elevated blood pressure is the main risk factor for stroke. Regarding SFA intake, some studies have observed little or no effect on stroke risk.1212. Siri-Tarino PW, Sun Q, Hu FB et al. Saturated fat, carbohydrate, and cardiovascular disease. Am J Clin Nutr. 2010;91(3):502-9. , 9696. Hooper L, Martin N, Abdelhamid A et al. Reduction in saturated fat intake for cardiovascular disease. Cochrane Database Syst Rev. 2015 Jun; (6):CD011737. , 223223. de Souza RJ, Mente A, Maroleanu A et al. Intake of saturated and trans unsaturated fatty acids and risk of all cause mortality, cardiovascular disease, and type 2 diabetes: Systematic review and meta-analysis of observational studies. BMJ. 2015 Aug; 351:h3978. , 224224. Jeppesen J, Hein HO, Suadicani P et al. Triglyceride concentration and ischemic heart disease: an eight-year follow-up in the Copenhagen male study. Circulation. 1998; 97(11):1029-36. In the WHI study, which followed women for about 8 years, reduced SFA intake did not reduce the risk of stroke.5959. Howard BV, Van Horn L, Hsia J et al. Low-fat dietary pattern and risk of cardiovascular disease: the Women’s Health Initiative Randomized Controlled Dietary Modification Trial. JAMA. 2006; 295(6):655-66.Conversely, other cohort studies, such as the Japan Collaborative Cohort Study for Evaluation of Cancer Risk (JACC), that followed 58 453 Japanese adults for 14 years,225225. Yamagishi K, Iso H, Yatsuya H et al; JACC Study Group. Dietary intake of saturated fatty acids and mortality from cardiovascular disease in Japanese: the Japan Collaborative Cohort Study for Evaluation of Cancer Risk (JACC) Study. Am J Clin Nutr. 2010; 92(4):759-65.and the PURE study,102102. Dehghan M, Mente A, Zhang X et al. Prospective Urban Rural Epidemiology (PURE) study investigators. Associations of fats and carbohydrate intake with cardiovascular disease and mortality in 18 countries from five continents (PURE): a prospective cohort study. Lancet. 2017; 390(10107):2050-62.reported an inverse association between SFA intake and stroke risk.

A meta-analysis found an inverse association between SFA intake and stroke risk only for Asian men with body mass index (BMI) <24 kg/m2, indicating that factors such as ethnicity, sex, and body weight influence the association between SFAs and stroke risk.226226. Cheng P, Wang J, Shao W et al. Can dietary saturated fat be beneficial in prevention of stroke risk? A meta-analysis. Neurol Sci. 2016; 37(7):1089-98.Thus, to date, there is no robust evidence to recommend the reduction of SFAs to prevent the risk of stroke.9696. Hooper L, Martin N, Abdelhamid A et al. Reduction in saturated fat intake for cardiovascular disease. Cochrane Database Syst Rev. 2015 Jun; (6):CD011737.

In randomized trials, the use of ω3 fatty acids, such as EPA, DHA and DPA (C20:5), reduced risk factors and mechanisms for cardiovascular events, including hypertension, hyperlipidemia, and endothelial dysfunction,213213. Geleijnse JM, Giltay EJ, Grobbee DE et al. Blood pressure response to fish oil supplementation: metaregression analysis of randomized trials. J Hypertens. 2002; 20(8):1493-9. , 227227. Mozaffarian D, Wu JHY. Omega-3 fatty acids and cardiovascular disease: effects on risk factors, molecular pathways, and clinical events. J Am Coll Cardiol. 2011; 58(20):2047-67. , 228228. Nobili V, Bedogni G, Alisi A et al. Docosahexaenoic acid supplementation decreases liver fat content in children with non-alcoholic fatty liver disease: double-blind randomised controlled clinical trial. Arch Dis Child. 2011; 96(4):350-3. suggesting their protective role in CVD. However, the impact of these fatty acids on ischemic stroke is still controversial. Observational studies have shown inverse associations between self-reported dietary ω3 intake and ischemic stroke,229229. Yaemsiri S, Sen S, Tinker LF et al. Serum fatty acids and incidence of ischemic stroke among postmenopausal women. Stroke. 2013; 44(10):2710-7.which were not confirmed in a meta-analysis of randomized trials using ω3 supplementation.227227. Mozaffarian D, Wu JHY. Omega-3 fatty acids and cardiovascular disease: effects on risk factors, molecular pathways, and clinical events. J Am Coll Cardiol. 2011; 58(20):2047-67.However, the meta-analysis data were derived from short-term supplementation studies of high-risk patients who, in general, had previous stroke, in which stroke was not a predetermined outcome. Therefore, it is not possible to generalize these results to populations in primary prevention.230230. Rizos EC, Ntzani EE, Bika E et al. Association between omega-3 fatty acid supplementation and risk of major cardiovascular disease events: a systematic review and meta-analysis. JAMA. 2012; 308(10):1024-33.In addition, ischemic stroke may be related to atherothrombotic or cardioembolic disease, whose pathophysiological mechanisms are different.231231. Iso H, Sato S, Umemura U et al. Linoleic acid, other fatty acids, and the risk of stroke. Stroke. 2002; 33(8):2086-93.DHA can reduce the risk of atherothrombotic stroke by reducing endothelial dysfunction and atherosclerosis, whereas EPA and DPA can have a greater impact on cardioembolic stroke due to their effects on coagulation and atrial fibrillation.232232. Mozaffarian D, Lemaitre RN, King IB et al. Circulating long- chain ω-3 fatty acids and incidence of congestive heart failure in older adults: the cardiovascular health study: a cohort study. Ann Intern Med. 2011; 155(3):160-70.Moreover, almost all studies of ω3 intake and stroke risk were based on self-reported dietary intake of these fatty acids, making it impossible to distinguish between the types of fatty acid consumed.

In a systematic review of 3 large US cohorts, the CHS, NHS and HPFS, the circulating levels of fatty acids were measured at baseline to assess their relationship with the incidence of ischemic stroke. Ischemic strokes were prospectively adjudicated and classified into atherothrombotic or cardioembolic, and the risk was calculated according to the circulating levels of fatty acids. Higher circulating levels of DHA were inversely associated with the incidence of atherothrombotic stroke, and DPA, with cardioembolic stroke. There was no association between EPA and stroke. These findings suggest differential benefits according to the ω3 fatty acid involved.233233. Saber H, Yakoob MY, Shi P et al. Omega-3 fatty acids and incident ischemic stroke and its atherothrombotic and cardioembolic subtypes in 3 US cohorts. Stroke. 2017; 48(10):2678-85.

7. Inflammation

SFAs are essential components of the lipid A present in the cell wall of Gram-negative bacteria – it is the endotoxic portion of lipopolysaccharide (LPS).234234. Banoub JH, El Aneed A, Cohen AM et al. Structural investigation of bacterial lipopolysaccharides by mass spectrometry and tandem mass spectrometry. Mass Spectrom Rev. 2010; 29(4):606-50.It is well documented that SFAs trigger inflammatory signaling, as they modulate both the NF-kB pathway, through the structure of TLR4 receptors,235235. Hwang DH, Kim JA, Lee JY. Mechanisms for the activation of Toll-like receptor 2/4 by saturated fatty acids and inhibition by docosahexaenoic acid. Eur J Pharmacol. 2016 Aug; 785:24-35.and the TLR2 pathway.236236. Huang S, Rutkowsky JM, Snodgrass RG et al. Saturated fatty acids activate TLR-mediated proinflammatory signaling pathways. J Lipid Res. 2012; 53(9):2002-13.Another mechanism that enhances the inflammatory process induced by SFA intake is intracellular NLRP3 inflammasome activation. The activated inflammasome then processes IL-1β and IL-18 into their mature forms, induced by NF-kB. Dietary SFAs have been shown to activate this mechanism via TLR4 receptors,237237. Reynolds CM, McGillicuddy FC, Harford KA et al. Dietary saturated fatty acids prime the NLRP3 inflammasome via TLR4 in dendritic cells-implications for diet-induced insulin resistance. Mol Nutr Food Res. 2012; 56(8):1212-22.as have prostaglandins E2 (PGE2) derived from arachidonic acid,238238. Wang Y, Tao J, Yao Y. Prostaglandin E2 activates NLRP3 inflammasome in endothelial cells to promote diabetic retinopathy. Horm Metab Res. 2018; 50(9):704-710.with important implications for coronary heart disease239239. Satoh M, Tabuchi T, Itoh T et al. NLRP3 inflammasome activation in coronary artery disease: results from prospective and randomized study of treatment with atorvastatin or rosuvastatin. Clin Sci (Lond). 2014; 126(3):233-41.and comorbidities associated with T2D, such as diabetic retinopathy.238238. Wang Y, Tao J, Yao Y. Prostaglandin E2 activates NLRP3 inflammasome in endothelial cells to promote diabetic retinopathy. Horm Metab Res. 2018; 50(9):704-710.

In macrophages, lauric acid240240. Suzuki M, Takaishi S, Nagasaki M et al. Medium-chain fatty acid-sensing receptor, GPR84, is a proinflammatory receptor. J Biol Chem. 2013; 288(15):10684-91showed greater inflammatory capacity, as assessed by the activation of the TLR4 pathway, compared to myristic, palmitic, and stearic acids, whereas MUFAs and PUFAs did not activate this pathway. The pretreatment of cells with different UFAs significantly reduced the pro-inflammatory effect induced by lauric acid.241241. Lee JY, Sohn KH, Rhee SH et al. Saturated fatty acids, but not unsaturated fatty acids, induce the expression of cyclooxygenase-2 mediated through Toll-like receptor 4. J Biol Chem. 2001; 276(20):16683-9. , 242242. Lee JY, Zhao L, Youn HS et al. Saturated fatty acid activates but polyunsaturated fatty acid inhibits Toll-like receptor 2 dimerized with Toll-like receptor 6 or 1. J Biol Chem. 2004; 279(17):16971-9. Also, inhibition of TLR2 expression improved insulin action in muscle cells treated with palmitic acid as well as in skeletal muscle and adipose tissue in mice fed a high-SFA diet.243243. Caricilli AM, Nascimento PH, Pauli JR et al. Inhibition of toll-like receptor 2 expression improves insulin sensitivity and signalling in muscle and white adipose tissue of mice fed a high-fat diet. J Endocrinol. 2008; 199(3):399-406.A study of 965 healthy young adults showed a positive association of plasma levels of myristic and palmitic acids with CRP levels, whereas stearic and linoleic acids were inversely associated.244244. Perreault M, Roke K, Badawi A et al. Plasma levels of 14:0, 16:0, 16:1n-7, and 20:3n-6 are positively associated, but 18:0 and 18:2n-6 are inversely associated with markers of inflammation in young healthy adults. Lipids. 2014; 49(3):255-63.

As precursors of eicosanoids and other anti-inflammatory mediators, ω3 fatty acids can exert anti-inflammatory effects, with benefits in several pathological conditions, including CVD. Many experimental studies have shown a wide range of ω3 anti-inflammatory effects, but in vivo investigations in humans have shown conflicting results.154154. Saravanan P, Davidson NC, Schmidt EB et al. Cardiovascular effects of marine omega-3 fatty acids. Lancet. 2010; 376(9740):540-50. , 245245. de Roos B, Mavrommatis Y, Brouwer IA. Long-chain n-3 polyunsaturated fatty acids: new insights into mechanisms relating to inflammation and coronary heart disease. Br J Pharmacol. 2009; 158(2):413-28.

PUFAs of the ω3 series, such as EPA and DHA, are precursors of anti-inflammatory eicosanoids with cardiovascular benefits. Although experimental studies have demonstrated the anti-inflammatory effects of ω3, some studies in humans have shown conflicting results regarding cardiovascular outcomes.133133. Abdelhamid AS, Brown TJ, Brainard JS, Biswas P, Thorpe GC, Moore HJ, et al. Omega-3 fatty acids for the primary and secondary prevention of cardiovascular disease. Cochrane Database of Syst Rev. 2018 Jul; (11):CD003177. , 154154. Saravanan P, Davidson NC, Schmidt EB et al. Cardiovascular effects of marine omega-3 fatty acids. Lancet. 2010; 376(9740):540-50. , 245245. de Roos B, Mavrommatis Y, Brouwer IA. Long-chain n-3 polyunsaturated fatty acids: new insights into mechanisms relating to inflammation and coronary heart disease. Br J Pharmacol. 2009; 158(2):413-28.

In cross-sectional and cohort studies, dietary intake of marine ω3 was associated with lower plasma levels of inflammatory markers, including adhesion molecules and CRP.246246. Lopez-Garcia E, Schulze MB, Manson JE et al. Consumption of (n-3) fatty acids is related to plasma biomarkers of inflammation and endothelial activation in women. J Nutr. 2004;134(7):1806-11. , 247247. Niu K, Hozawa A, Kuriyama S et al. Dietary long-chain n-3 fatty acids of marine origin and serum C-reactive protein concentrations are associated in a population with a diet rich in marine products. Am J Clin Nutr. 2006; 84(1):223-9. Concentrations of marine ω3 in plasma and in erythrocyte or granulocyte membranes were inversely associated with CRP concentrations in healthy individuals or patients with stable CAD.248248. Micallef MA, Munro IA, Garg ML. An inverse relationship between plasma n-3 fatty acids and C-reactive protein in healthy individuals. Eur J Clin Nutr. 2009; 63(9):1154-6.

249. Farzaneh-Far R, Harris WS, Garg S et al. Inverse association of erythrocyte n-3 fatty acid levels with inflammatory biomarkers in patients with stable coronary artery disease: the Heart and Soul Study. Atherosclerosis. 2009; 205(2):538-43.
- 250250. Madsen T, Skou HA, Hansen VE et al. C-reactive protein, dietary n-3 fatty acids, and the extent of coronary artery disease. Am J Cardiol. 2001; 88(10):1139-42. An intervention study showed that food containing marine ω3 or supplementation with fish oil or DHA produced results compatible with attenuation of the inflammatory response in patients with T2D and hypertriglyceridemia.251251. Kelley DS, Siegel D, Fedor DM et al. DHA supplementation decreases serum C-reactive protein and other markers of inflammation in hypertriglyceridemic men. J Nutr. 2009; 139(3):495-501.

252. Murphy KJ, Meyer BJ, Mori TA et al. Impact of foods enriched with n-3 long-chain polyunsaturated fatty acids on erythrocyte n-3 levels and cardiovascular risk factors. Br J Nutr. 2007; 97(4):749-57.
- 253253. Rizza S, Tesauro M, Cardillo C et al. Fish oil supplementation improves endothelial function in normoglycemic offspring of patients with type 2 diabetes. Atherosclerosis. 2009; 206(2):569-74. In other trials, a diet supplemented with ω3 did not cause significant changes in inflammatory parameters in patients with cardiometabolic risk (1.24 g/day)254254. Petersson H, Risérus U, McMonagle J et al. Effects of dietary fat modification on oxidative stress and inflammatory markers in the LIPGENE study. Br J Nutr. 2010; 104(9):1357-62.or in patients with previous AMI (5.2 g/day),255255. Madsen T, Christensen JH, Schmidt EB. C-reactive protein and n-3 fatty acids in patients with a previous myocardial infarction: a placebo-controlled randomized study. Eur J Nutr. 2007; 46(7):428-30. , 256256. Madsen T, Christensen JH, Blom M et al. The effect of dietary n-3 fatty acids on serum concentrations of C-reactive protein: a dose-response study. Br J Nutr. 2003; 89(4):517-22. and the same was observed with PUFA supplementation in plasma CRP concentrations of healthy individuals (2.0 or 6.6 g/day).256256. Madsen T, Christensen JH, Blom M et al. The effect of dietary n-3 fatty acids on serum concentrations of C-reactive protein: a dose-response study. Br J Nutr. 2003; 89(4):517-22.Differences in the population profile, route of administration, supplementation dose, concomitant use of statins, and analyzed parameters may have contributed to the discrepant results. Therefore, the real clinical relevance of the anti-inflammatory effects of ω3 fatty acids of marine origin is still uncertain.

Studies involving ALA have shown an inverse relationship between ALA intake and inflammatory parameters, including serum CRP.246246. Lopez-Garcia E, Schulze MB, Manson JE et al. Consumption of (n-3) fatty acids is related to plasma biomarkers of inflammation and endothelial activation in women. J Nutr. 2004;134(7):1806-11. , 257257. Yoneyama S, Miura K, Sasaki S et al. Dietary intake of fatty acids and serum C-reactive protein in Japanese. J Epidemiol. 2007; 17(3):86-92. , 258258. Poudel-Tandukar K, Nanri A, Matsushita Y et al. Dietary intakes of alpha-linolenic and linoleic acids are inversely associated with serum C-reactive protein levels among Japanese men. Nutr Res. 2009; 29(6):363-370. ALA supplementation reduced the concentration of inflammatory markers in patients with dyslipidemia, which occurred especially when the baseline diet was high in SFAs and low in MUFAs.259259. Rallidis LS, Paschos G, Liakos GK et al. Dietary alpha-linolenic acid decreases C-reactive protein, serum amyloid A and interleukin-6 in dyslipidaemic patients. Atherosclerosis. 2003; 167(2):237-242

Trans fat intake was positively associated with systemic inflammation, characterized by an increase in IL-1β, IL-6, TNF-α, and monocyte chemoattractant protein (MCP) levels in patients with CVD.260260. Mozaffarian D, Rimm EB, King IB et al. Trans fatty acids and systemic inflammation in heart failure. AmJ Clin Nutr. 2004; 80(6):1521-5.A case-control study of 111 patients with CAD showed that the incorporation of trans fatty acids into erythrocytes was associated with higher plasma levels of CRP and IL-6.7777. Hadj Ahmed S, Kharroubi W, Kaoubaa N et al. Correlation of trans fatty acids with the severity of coronary artery disease lesions. Lipids Health Dis. 2018; 17(1):52.

8. Insulin Resistance and Diabetes

Inflammatory signaling induced by SFA intake can activate proteins with serine kinase activity, such as c-Jun N-terminal kinase (JNK) and IKK. These proteins negatively interfere with insulin signal transduction by reducing tyrosine phosphorylation of IRS-1.261261. Holland WL, Bikman BT, Wang LP et al. Lipid-induced insulin resistance mediated by the proinflammatory receptor TLR4 requires saturated fatty acid-induced ceramide biosynthesis in mice. J Clin Invest. 2011; 121(5):1858-70. , 262262. Patel PS, Buras ED, Balasubramanyam A. The role of the immune system in obesity and insulin resistance. J Obes. 2013; 2013:616193.

Intake of a high-SFA diet for 3 months reduced insulin sensitivity in individuals without diabetes.263263. Vessby B, Uusitupa M, Hermansen K et al. Substituting dietary saturated for monounsaturated fat impairs insulin sensitivity in healthy men and women: the KANWU Study. Diabetologia. 2001; 44(3):312-9.In the LIPGENE cohort study, which evaluated 417 individuals with metabolic syndrome, reduced SFA intake had no impact on fasting plasma glucose and insulin concentrations, homeostasis model assessment of insulin resistance (HOMA-IR), insulin sensitivity, and inflammatory markers.264264. Tierney AC1, McMonagle J, Shaw DI et al. Effects of dietary fat modification on insulin sensitivity and on other risk factors of the metabolic syndrome – LIPGENE: a European randomized dietary intervention study. Int J Obes (Lond). 2011; 35(6):800-9.It is worth noting that, in the LIPGENE study, energy from SFAs was replaced with energy from UFAs or complex carbohydrates. In the Reading, Imperial, Surrey, Cambridge, and Kings (RISCK) trial, involving 548 overweight participants with high cardiometabolic risk, the isocaloric replacement of a SFA-rich diet (with high glycemic index) with a MUFA-rich diet (with high or low glycemic index) for 6 months caused no change in insulin sensitivity.265265. Jebb SA, Lovegrove JA, Griffin BA et al; RISCK Study Group. Effect of changing the amount and type of fat and carbohydrate on insulin sensitivity and cardiovascular risk: the RISCK (Reading, Imperial, Surrey, Cambridge, and Kings) trial. Am J Clin Nutr. 2010; 92(4):748–758.However, it was demonstrated that diets enriched with SFAs, especially palmitic acid, acutely induced insulin resistance in individuals with and without glucose intolerance.266266. Koska J, Ozias MK, Deer J et al. A human model of dietary saturated fatty acid induced insulin resistance. Metabolism. 2016; 65(11):1621-1628.

Prospective studies have found a positive association between SFA intake and glucose intolerance.267267. Feskens EJ, Virtanen SM, Räsänen L et al. Dietary factors determining diabetes and impaired glucose tolerance. A 20-year follow-up of the Finnish and Dutch cohorts of the Seven Countries Study. Diabetes Care. 1995; 18(8):1104-12. , 268268. Mayer EJ1, Newman B, Quesenberry CP Jr et al. Usual dietary fat intake and insulin concentrations in healthy women twins. Diabetes Care. 1993; 16(11):1459-1469. The HPFS study, which included 42 504 men, found an association of total fat and SFA intake with an increased risk of T2D, but the association was dependent of BMI.269269. van Dam RM, Willett WC, Rimm EB et al. Dietary fat and meat intake in relation to risk of type 2 diabetes in men. Diabetes Care. 2002; 25(3):417-424.In the Iowa Women’s Health Study,270270. Meyer KA, Kushi LH, Jacobs DR Jr et al. Dietary fat and incidence of type 2 diabetes in older Iowa women. Diabetes Care. 2001; 24(9):1528-35involving 35 988 women without a previous diagnosis of T2D, SFA intake was not associated with the risk of T2D; however, the risk of diabetes was inversely related to the replacement of SFAs with PUFAs. In addition, consumption of animal fat was associated with a 20% increase in T2D risk.270270. Meyer KA, Kushi LH, Jacobs DR Jr et al. Dietary fat and incidence of type 2 diabetes in older Iowa women. Diabetes Care. 2001; 24(9):1528-35Another prospective study, the NHS study, which assessed the relationship between fat intake and T2D risk in 84 204 women, concluded that total fat and SFA intake was not associated with an increased risk of T2D.271271. Salmerón J, Hu FB, Manson JE et al. Dietary fat intake and risk of type 2 diabetes in women. Am J Clin Nutr. 2001; 73(6):1019-1026.

The WHI trial investigated the effects of dietary intervention in postmenopausal women followed for about 8 years and found that reduced intakes of total fat (9.1% of energy) and SFAs (3.2% of energy) did not change the risk of developing T2D. It is worth noting that the reduction in fat intake was offset by a 10% increase in carbohydrate intake.272272. Tinker LF1, Bonds DE, Margolis KL et al; Women’s Health Initiative. Low-fat dietary pattern and risk of treated diabetes mellitus in postmenopausal women: the Women’s Health Initiative randomized controlled dietary modification trial. Arch Intern Med. 2008; 168(14):1500-1511.

The development of T2D is known to result from the interaction of genetic factors and lifestyle, such as diet. The EPIC-InterAct study273273. Li SX, Imamura F, Schulze MB et al. Interplay between genetic predisposition, macronutrient intake and type 2 diabetes incidence: analysis within EPIC-InterAct across eight European countries. Diabetologia. 2018; 61(6):1325-1332.evaluated potential interactions of genetic susceptibility and the effect of macronutrient intake on the risk of developing T2D and reported that SFA intake was not associated with T2D risk. Also, genetic susceptibility to T2D did not influence the relationship between macronutrient intake and T2D risk.273273. Li SX, Imamura F, Schulze MB et al. Interplay between genetic predisposition, macronutrient intake and type 2 diabetes incidence: analysis within EPIC-InterAct across eight European countries. Diabetologia. 2018; 61(6):1325-1332.In another cohort of the EPIC-InterAct study, investigating the association between T2D risk and the concentration of different fatty acids in plasma phospholipids,1414. Forouhi NG, Koulman A, Sharp SJ et al. Differences in the prospective association between individual plasma phospholipid saturated fatty acids and incident type 2 diabetes: the EPIC-InterAct case-cohort study. Lancet Diabetes Endocrinol. 2014; 2(10):810-8.myristic, stearic, and palmitic acids were positively associated with T2D risk. It should be noted that a higher plasma concentration of these fatty acids was positively associated with the intakes of alcohol, margarine, and soft drinks and negatively with the intakes of fruit and vegetables, olive oil, and vegetable oil. Pentadecanoic acid (15:0) and heptadecanoic acid (17:0), however, were positively associated with the intakes of milk and dairy products, nuts, cakes, and fruit and vegetables and inversely associated with T2D risk.1414. Forouhi NG, Koulman A, Sharp SJ et al. Differences in the prospective association between individual plasma phospholipid saturated fatty acids and incident type 2 diabetes: the EPIC-InterAct case-cohort study. Lancet Diabetes Endocrinol. 2014; 2(10):810-8.Therefore, the observed deleterious effects cannot be attributed solely to the isolated activity of these SFAs, but rather to a context of inadequate diet.

A meta-analysis of observational studies found no association between SFA intake and T2D risk.223223. de Souza RJ, Mente A, Maroleanu A et al. Intake of saturated and trans unsaturated fatty acids and risk of all cause mortality, cardiovascular disease, and type 2 diabetes: Systematic review and meta-analysis of observational studies. BMJ. 2015 Aug; 351:h3978.In a meta-analysis of cohort studies investigating the association between dietary patterns and T2D risk, a reduction in the risk of T2D was associated with healthy eating patterns, and not with a specific macronutrient.274274. Alhazmi A, Stojanovski E, McEvoy M et al. Diet quality score is a predictor of type 2 diabetes risk in women: the Australian Longitudinal Study on Women’s Health. Br J Nutr. 2014; 112(6):945-51.In a meta-analysis of dietary intervention controlled studies evaluating the effect of isocaloric replacement of macronutrients on plasma glucose and insulin concentrations and on insulin resistance-related parameters, the replacement of SFAs with PUFAs reduced the glucose levels, glycated hemoglobin (HbA1c), C-peptide, and HOMA.109109. Imamura F, Sharp SJ, Koulman A et al. A combination of plasma phospholipid fatty acids and its association with incidence of type 2 diabetes: The EPIC-InterAct case-cohort study. PLoS Med. 2017; 14(10):e1002409.

To date, the evidence on the impact of SFAs on T2D risk is inconclusive. Results indicate that the influence of other dietary nutrients and components cannot be discarded, which is in line with international and Brazilian dietary guidelines. Therefore, the adoption of healthy eating patterns is recommended. Priority should be given to the consumption of fruit and vegetables, dairy products, lean meats, and complex carbohydrates, with low intake of simple carbohydrates, processed meats, and ultra-processed foods—such diet is considered more efficient in reducing the risk of cardiometabolic diseases.

Prospective cohort studies involving a large number of participants have suggested that a higher intake of ω3 fatty acids is associated with a higher incidence of T2D.270270. Meyer KA, Kushi LH, Jacobs DR Jr et al. Dietary fat and incidence of type 2 diabetes in older Iowa women. Diabetes Care. 2001; 24(9):1528-35 , 275275. Kaushik M, Mozaffarian D, Spiegelman D et al. Long-chain omega-3 fatty acids, fish intake, and the risk of type 2 diabetes mellitus. Am J Clin Nutr. 2009; 90(3):613-20. However, in a meta-analysis evaluating the relationship between marine ω3 PUFAs and T2D risk,276276. Wu JHY, Micha R, Imamura F et al. Omega-3 fatty acids and incident type 2 diabetes: a systematic review and meta-analysis. Br J Nutr. 2012; 107(Suppl 2):S214-27.both the intake of fish and crustaceans (13 studies, RR per 100 g of fish/day = 1.12, 95% CI: 0.94-1.34) and supplementation with EPA+DHA (16 cohorts, RR per 250 mg/day = 1.04, 95% CI: 0.97-1.10) were not associated with the risk of diabetes. Plasma concentrations of EPA+DHA (5 cohorts, RR per 3% of total fatty acids = 0.94, 95% CI: 0.75-1.17) were also not associated with T2D risk.276276. Wu JHY, Micha R, Imamura F et al. Omega-3 fatty acids and incident type 2 diabetes: a systematic review and meta-analysis. Br J Nutr. 2012; 107(Suppl 2):S214-27.Given the heterogeneity between studies and inconsistent effects related to follow-up duration, there is no evidence of beneficial or harmful effects of fish/seafood intake or EPA+DHA supplementation on the risk of developing diabetes.

However, there is evidence that higher plasma EPA/DHA levels may be associated with a lower risk of new-onset diabetes.277277. Djoussé L, Biggs ML, Lemaitre RN et al. Plasma omega-3 fatty acids and incident diabetes in older adults. Am J Clin Nutr. 2011; 94(2):527-33.Despite the benefits described after ω3 intake in patients with T2D, a meta-analysis involving 23 randomized controlled trials showed no significant changes in HbA1c, fasting glucose, or fasting insulin when ω3 was supplemented at a mean dose of 3.5 g/day.8686. Hartweg J, Perera R, Montori V et al. Omega-3 polyunsaturated fatty acids (PUFA) for type 2 diabetes mellitus. Cochrane Database Syst Rev. 2008 Jan;(1):CD003205.. Likewise, another meta-analysis of 26 controlled trials found that fish-oil supplementation, ranging from 2 to 22 g/day, did not change plasma HbA1c levels in patients with diabetes;278278. Friedberg CE, Janssen MJ, Heine RJ et al. Fish oil and glycemic control in diabetes: a meta-analysis. Diabetes Care. 1998; 21(4):494-500.however, the high doses used in the studies should be taken into consideration. In addition, the Outcome Reduction with an Initial Glargine Intervention (ORIGIN) trial showed that ω3 supplementation did not reduce the rate of cardiovascular events in patients with glucose intolerance, impaired fasting glucose, and T2D.279279. ORIGIN Trial Investigators, Bosch J, Gerstein HC, Dagenais GR et al. n-3 fatty acids and cardiovascular outcomes in patients with dysglycemia. N Engl J Med. 2012; 367(4):309-18.

The effects of ALA on the glycemic profile have also been inconsistent.217217. Hall WL, Sanders KA, Sanders TA et al. A high-fat meal enriched with eicosapentaenoic acid reduces postprandial arterial stiffness measured by digital volume pulse analysis in healthy men. J Nutr. 2008; 138(2):287-91.However, it has been suggested that ALA intake may benefit glucose metabolism. Prospective data from the CHS study showed that higher plasma ALA levels were associated with a lower risk of new-onset T2D.277277. Djoussé L, Biggs ML, Lemaitre RN et al. Plasma omega-3 fatty acids and incident diabetes in older adults. Am J Clin Nutr. 2011; 94(2):527-33.Similarly, in a large prospective analysis of more than 43 000 Chinese adults, ALA intake was inversely associated with the risk of incident T2D.280280. Brostow DP, Odegaard AO, Koh WP et al. Omega-3 fatty acids and incident type 2 diabetes: the Singapore Chinese Health Study. Am J Clin Nutr. 2011; 94(2):520-6.In a systematic review and meta-analysis of randomized controlled trials, ALA supplementation reduced blood glucose by 3.6 mg/dL.6767. Wendland E, Farmer A, Glasziou P et al. Effect of alpha linolenic acid on cardiovascular risk markers: a systematic review. Heart. 2006; 92(2):166-9.Regarding flaxseed, a randomized controlled trial showed an improvement in insulin sensitivity.281281. Bloedon LT, Balikai S, Chittams J et al. Flaxseed and cardiovascular risk factors: results from a double blind, randomized, controlled clinical trial. J Am Coll Nutr. 2008; 27(1):65-74.

A systematic review identified 16 prospective studies, including cohort studies, that evaluated the relationship of ω3 intake and plasma levels with the incidence of T2D. Of a total of 540 184 individuals, 25 670 were cases of incident T2D.276276. Wu JHY, Micha R, Imamura F et al. Omega-3 fatty acids and incident type 2 diabetes: a systematic review and meta-analysis. Br J Nutr. 2012; 107(Suppl 2):S214-27.Both ALA intake (n = 7 studies) and plasma ALA concentration (n = 6 studies) were not associated with T2D risk. Moderate heterogeneity (<55%) was observed for circulating ALA levels and diabetes, which may suggest a slightly lower risk of T2D.276276. Wu JHY, Micha R, Imamura F et al. Omega-3 fatty acids and incident type 2 diabetes: a systematic review and meta-analysis. Br J Nutr. 2012; 107(Suppl 2):S214-27.

A review on ω3 fatty acids, cardiometabolic risk, and T2D concluded that there are no data demonstrating that ALA reduces the conversion of cardiometabolic risk to T2D or reduces mortality in people with T2D or cardiometabolic risk. ALA appears to reduce platelet aggregation in people with diabetes.282282. Barre DE. The role of consumption of alpha-linolenic, eicosapentaenoic and docosahexaenoic acids in human metabolic syndrome and type 2 diabetes: a mini-review. J Oleo Sci. 2007; 56(7):319-25.

Observational studies, using biological markers of fat intake or dietary surveys, suggest an inverse association between ω6 intake and T2D risk, although the data are not always consistent.271271. Salmerón J, Hu FB, Manson JE et al. Dietary fat intake and risk of type 2 diabetes in women. Am J Clin Nutr. 2001; 73(6):1019-1026. , 283283. Lichtenstein AH, Schwab US. Relationship of dietary fat to glucose metabolism. Atherosclerosis. 2000; 150(2):227-43. In the NHS study, involving 84 204 women aged 34 to 59 years without diabetes, CVD, or cancer who were prospectively followed for 6 years,ω6 intake assessed by validated food-frequency questionnaires was associated with a lower risk of T2D.271271. Salmerón J, Hu FB, Manson JE et al. Dietary fat intake and risk of type 2 diabetes in women. Am J Clin Nutr. 2001; 73(6):1019-1026.In men, a large prospective study, the HPFS study, also showed that the intake of ω6 as linoleic acid was associated with a lower risk of T2D in those aged <65 years and with BMI <25 kg/m22. World Health Organization (WHO). Global Health Observatory. [Cited in 2019 Dec 12]. Available from: https://www.who.int/gho/ncd/mortality_morbidity/en/
https://www.who.int/gho/ncd/mortality_mo...
.269269. van Dam RM, Willett WC, Rimm EB et al. Dietary fat and meat intake in relation to risk of type 2 diabetes in men. Diabetes Care. 2002; 25(3):417-424.Also, in the Singapore Chinese Health Study, in which more than 43 000 Chinese adults were prospectively assessed, neither ω6 intake nor the ω6/ω3 ratio was associated with new-onset T2D.280280. Brostow DP, Odegaard AO, Koh WP et al. Omega-3 fatty acids and incident type 2 diabetes: the Singapore Chinese Health Study. Am J Clin Nutr. 2011; 94(2):520-6.

Data from small intervention studies are also conflicting regarding the effect of ω6 on insulin sensitivity.284284. Heine RJ, Mulder C, Popp-Snijders C et al. Linoleic-acid-enriched diet: long-term effects on serum lipoprotein and apolipoprotein concentrations and insulin sensitivity in noninsulin- dependent diabetic patients. Am J Clin Nutr. 1989; 49(3):448-56.Further long-term, controlled studies are needed to identify the best dietary fatty acid composition to reduce the risk of T2D. Few data are available, and the effects of dietary fatty acid types (PUFAs and SFAs) on glycemic control in people with diabetes remain uncertain.285285. Risérus U, Willett WC, Hu FB. Dietary fats and prevention of type 2 diabetes. Prog Lipid Res. 2009; 48(1):44-51.

Regarding trans fatty acids, experimental studies have shown adverse effects on glucose homeostasis and development of diabetes.286286. Zhao X, Shen C, Zhu H et al. Trans-fatty acids aggravate obesity, insulin resistance and hepatic steatosis in C57BL/6 mice, possibly by suppressing the IRS1 dependent pathway. Molecules. 2016; 21(6):1-11.

287. Dorfman SE, Laurent D, Gounarides JS et al. Metabolic implications of dietary trans-fatty acids. Obesity. 2009; 17(6):1200-7.
- 288288. Thompson AK, Minihane AM, Williams CM. Trans fatty acids, insulin resistance and diabetes. Eur J Clin Nutr. 2011; 65(5):553-64. In addition, trans fatty acids increase plasma levels of TG, insulin, and postprandial glucose289289. Longhi R. Effect of a trans fatty acid-enriched diet on biochemical and inflammatory parameters in Wistar rats. Eur J Nutr. 2017; 56(4):1003-16.and reduce glucose uptake by the skeletal muscle—changes that are accompanied by increased visceral and hepatic fat.287287. Dorfman SE, Laurent D, Gounarides JS et al. Metabolic implications of dietary trans-fatty acids. Obesity. 2009; 17(6):1200-7.A study using data from the NHANES survey to investigate the association between trans fatty acids and metabolic syndrome found that plasma trans-fatty-acid concentration was positively associated with risk of metabolic syndrome and its individual components.290290. Zhang Z, Gillespie C, Yang Q. Plasma trans-fatty acid concentrations continue to be associated with metabolic syndrome among US adults after reductions in trans-fatty acid intake. Nutr Res. 2017 Jul; 43:51-9.Even in small amounts, trans fatty acids have deleterious effects on glucose homeostasis, stimulating glycogenesis and increasing visceral fat.286286. Zhao X, Shen C, Zhu H et al. Trans-fatty acids aggravate obesity, insulin resistance and hepatic steatosis in C57BL/6 mice, possibly by suppressing the IRS1 dependent pathway. Molecules. 2016; 21(6):1-11. , 289289. Longhi R. Effect of a trans fatty acid-enriched diet on biochemical and inflammatory parameters in Wistar rats. Eur J Nutr. 2017; 56(4):1003-16. Consumption of a trans fat-rich diet has been shown to induce greater weight gain, hepatic steatosis, and insulin resistance by suppressing the IRS-1 signaling pathway, with a consequent reduction in Akt and protein kinase C (PKC) phosphorylation.286286. Zhao X, Shen C, Zhu H et al. Trans-fatty acids aggravate obesity, insulin resistance and hepatic steatosis in C57BL/6 mice, possibly by suppressing the IRS1 dependent pathway. Molecules. 2016; 21(6):1-11.In overweight patients with T2D, the intake of trans fatty acids has been consistently correlated with reduced insulin sensitivity and increased postprandial glucose and insulinemia.291291. Christiansen E, Schnider S, Palmvig B et al. Intake of a diet high in trans monounsaturated fatty acids or saturated fatty acids: Effects on postprandial insulinemia and glycemia in obese patients with NIDDM. Diabetes Care. 1997; 20(5):881-7.

The CHS study, investigating the association of the incidence of T2D with both plasma phospholipid trans fat concentration and their consumption, found that plasma trans fatty acid concentrations were positively associated with the incidence of T2D after correction for de novo lipogenesis.292292. Wang Q, Imamura F, Ma W et al. Circulating and dietary trans fatty acids and incident type 2 diabetes in older adults: The cardiovascular health study. Diabetes Care. 2015; 38(6):1099-107.However, after adjusting for the intake of other foods, trans fatty acid intake was not associated with the incidence of T2D.292292. Wang Q, Imamura F, Ma W et al. Circulating and dietary trans fatty acids and incident type 2 diabetes in older adults: The cardiovascular health study. Diabetes Care. 2015; 38(6):1099-107.An important systematic review showed that trans fat intake was associated with a 28% increase in the risk of T2D, when studies with a low risk of bias were analyzed, in addition to being associated with increased all-cause mortality (34%), coronary heart disease mortality (28%), and cardiovascular risk (21%).223223. de Souza RJ, Mente A, Maroleanu A et al. Intake of saturated and trans unsaturated fatty acids and risk of all cause mortality, cardiovascular disease, and type 2 diabetes: Systematic review and meta-analysis of observational studies. BMJ. 2015 Aug; 351:h3978.

9. Fatty Liver Disease

9.1. Hepatic Steatosis

The liver has a great metabolic capacity for the metabolism of all nutrients, especially fats. However, intracellular TG accumulation in more than 5% of hepatocytes characterizes nonalcoholic fatty liver disease (NAFLD),293293. Leclercq IA, Horsmans Y. Nonalcoholic fatty liver disease: the potential role of nutritional management. Curr Opin Clin Nutr Metab Care. 2008; 11(6):766-73.a broad-spectrum clinical condition that initiates with hepatic steatosis and then progresses to nonalcoholic steatohepatitis (NASH), marked by the presence of fat and inflammatory infiltrate. This condition predisposes the person to the appearance of hepatic complications, such as fibrosis, cirrhosis, and hepatocellular carcinoma,294294. Benedict M, Zhang X. Non-alcoholic fatty liver disease: An expanded review. World J Hepatol. 2017; 9(16):715-32. , 295295. Serfaty L, Lemoine M. Definition and natural history of metabolic steatosis: clinical aspects of NAFLD, NASH and cirrhosis. Diabetes Metab. 2008; 34(6 Pt 2):634-7. and extrahepatic complications, such as CVD and T2D.296296. Haas JT, Francque S, Staels B. Pathophysiology and mechanisms of nonalcoholic fatty liver disease. Annu Rev Physiol. 2016 Nov; 78:181-205.The diagnosis should exclude secondary causes of hepatic steatosis, such as alcohol abuse, viral or autoimmune hepatitis, or steatosis due to use of steatogenic drugs.296296. Haas JT, Francque S, Staels B. Pathophysiology and mechanisms of nonalcoholic fatty liver disease. Annu Rev Physiol. 2016 Nov; 78:181-205. , 297297. Chalasani N, Younossi Z, Lavine JE et al. The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases. Hepatology. 2018; 67(1):328-57.

NAFLD is strongly associated with factors that compose the cardiometabolic risk profile, such as obesity, insulin resistance, T2D, and dyslipidemia.296296. Haas JT, Francque S, Staels B. Pathophysiology and mechanisms of nonalcoholic fatty liver disease. Annu Rev Physiol. 2016 Nov; 78:181-205. , 297297. Chalasani N, Younossi Z, Lavine JE et al. The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases. Hepatology. 2018; 67(1):328-57. About 90% of patients with NAFLD have at least one cardiometabolic risk factor, and 30% have all factors. The risk of NAFLD incidence has been shown to increase proportionally to the sum of factors related to cardiometabolic risk. For this reason, NAFLD is identified as the hepatic manifestation of cardiometabolic risk.298298. Targher G, Arcaro G. Non-alcoholic fatty liver disease and increased risk of cardiovascular disease. Atherosclerosis. 2007; 191(2):235-40.Individuals with T2D are at a 2-to-4-fold increased risk of progression to steatohepatitis together with the development of fatty liver disease complications.294294. Benedict M, Zhang X. Non-alcoholic fatty liver disease: An expanded review. World J Hepatol. 2017; 9(16):715-32.

The development of NAFLD is related to an increased influx of free fatty acids (FFAs) to the liver, mainly due to increased lipolysis in adipose tissue, associated with insulin resistance and excess calories in the diet.299299. Zivkovic AM, German JB, Sanyal AJ. Comparative review of diets for the metabolic syndrome: implications for nonalcoholic fatty liver disease. Am J Clin Nutr. 2007; 86(2):285-300.In patients with NAFLD, about 60% of hepatic TGs stem from adipose tissue lipolysis, 26% from de novo lipogenesis, and 14% from the diet.300300. Donnelly KL, Smith CI, Schwarzenberg SJ et al. Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J Clin Invest. 2005;115(5):1343-51.Additionally, there is an increase in hepatic lipogenesis together with a decrease in mitochondrial β-oxidation or VLDL secretion by the liver, contributing to hepatic lipid accumulation.301301. Fabbrini E, Mohammed BS, Magkos F et al. Alterations in adipose tissue and hepatic lipid kinetics in obese men and women with nonalcoholic fatty liver disease. Gastroenterology. 2008; 134(2):424-31. , 302302. Postic C, Girard J. The role of the lipogenic pathway in the development of hepatic steatosis. Diabetes Metab. 2008; 34(6 Pt 2):643-8. Hepatic lipid accumulation may then lead to inflammation, development of fibrosis, and loss of function. Fibrosis is the most important predictor of NAFLD-related mortality, and its presence increases the risk of death from CVD and liver diseases.296296. Haas JT, Francque S, Staels B. Pathophysiology and mechanisms of nonalcoholic fatty liver disease. Annu Rev Physiol. 2016 Nov; 78:181-205.

Other factors may be related to the progression of the disease, such as: 1) increased ROS generation, promoting oxidative stress due to mitochondrial dysfunction or ER stress;303303. Wei Y, Rector RS, Thyfault JP et al. Nonalcoholic fatty liver disease and mitochondrial dysfunction. World J Gastroenterol. 2008; 14(2):193-9.2) lipid peroxidation; 3) activation of inflammatory pathways with a consequent increase in hepatic secretion of cytokines and inflammatory mediators such as TNF-α and IL-6, which may deteriorate the condition.304304. Duvnjak M, Lerotić I, Barsić N et al. Pathogenesis and management issues for non-alcoholic fatty liver disease. World J Gastroenterol. 2007;13(34):4539-50.Moreover, lack of physical activity associated with a poor diet, i.e., rich in fats and excess calories, predisposes the development of NAFLD.305305. Lottenberg AM, Afonso Mda S, Lavrador MS et al. The role of dietary fatty acids in the pathology of metabolic syndrome. J Nutr Biochem. 2012; 23(9):1027-40.

Individuals with NAFLD have increased hepatic expression of genes related to fatty acid transport (fatty acid-binding proteins 4 and 5), TG hydrolysis (LPL), and recruitment of monocytes (MCP1) and PPAR-γ2.306306. Westerbacka J, Kolak M, Kiviluoto T, et al. Genes involved in fatty acid partitioning and binding, lipolysis, monocyte/macrophage recruitment, and inflammation are overexpressed in the human fatty liver of insulin-resistant subjects. Diabetes. 2007;56(11):2759-2765.PPAR-γ has been shown to induce SREBP-1c expression, with enhanced expression of genes that control proteins related to hepatic TG synthesis.307307. Pettinelli P, Videla LA. Up-regulation of PPAR-gamma mRNA expression in the liver of obese patients: an additional reinforcing lipogenic mechanism to SREBP-1c induction. J Clin Endocrinol Metab. 2011; 96(5):1424-30.

Studies in animal models308308. Machado RM, Stefano JT, Oliveira CP et al. Intake of trans fatty acids causes nonalcoholic steatohepatitis and reduces adipose tissue fat content. J Nutr. 2010; 140(6):1127-32. , 309309. Tetri LH, Basaranoglu M, Brunt EM et al. Severe NAFLD with hepatic necroinflammatory changes in mice fed trans fats and a high-fructose corn syrup equivalent. Am J Physiol Gastrointest Liver Physiol. 2008; 295(5):G987-95. or clinical trials using human participants306306. Westerbacka J, Kolak M, Kiviluoto T, et al. Genes involved in fatty acid partitioning and binding, lipolysis, monocyte/macrophage recruitment, and inflammation are overexpressed in the human fatty liver of insulin-resistant subjects. Diabetes. 2007;56(11):2759-2765. , 310310. van Herpen NA, Schrauwen Hinderling VB, Schaart G et al. Three weeks on a high-fat diet increases intrahepatic lipid accumulation anddecreases metabolic flexibility in healthy overweight men. J Clin Endocrinol Metab. 2011; 96(4):E691-5. have strongly demonstrated the participation of a high-fat diet in the induction of hepatic steatosis. Insulin resistance plays a major role in hepatic lipid accumulation311311. Cave M, Deaciuc I, Mendez C et al. Nonalcoholic fatty liver disease: predisposing factors and the role of nutrition. J Nutr Biochem. 2007; 18(3):184-95.and, within this context, the amount of fat (especially the type of fatty acid) influences hepatic lipogenesis and the action of insulin.301301. Fabbrini E, Mohammed BS, Magkos F et al. Alterations in adipose tissue and hepatic lipid kinetics in obese men and women with nonalcoholic fatty liver disease. Gastroenterology. 2008; 134(2):424-31.

302. Postic C, Girard J. The role of the lipogenic pathway in the development of hepatic steatosis. Diabetes Metab. 2008; 34(6 Pt 2):643-8.
- 303303. Wei Y, Rector RS, Thyfault JP et al. Nonalcoholic fatty liver disease and mitochondrial dysfunction. World J Gastroenterol. 2008; 14(2):193-9.

9.2. Saturated Fatty Acids and Nonalcoholic Steatohepatitis

In hepatocytes, stearic acid and palmitic acid are able to induce apoptosis via excess JNK activation.312312. Malhi H, Bronk SF, Werneburg NW et al. Free fatty acids induce JNK dependent hepatocyte lipoapoptosis. J Biol Chem. 2006; 281(17):12093-101.Another finding was that palmitate treatment can activate the IRE1α signaling pathway via TLR4. IRE1 is an ER transmembrane protein that governs the response to malformed proteins in the reticulum and induces apoptosis.313313. Shen C, Ma W, Ding L et al. The TLR4-IRE1α pathway activation contributes to palmitate-elicited lipotoxicity in hepatocytes. J Cell Mol Med. 2018; 22(7):3572-81.

A recent study demonstrated that palmitic acid promotes oxidative stress, ER stress, mitochondrial dysfunction, and inflammation in HepG2 cells. Animals that were given a high-fat diet rich in SFAs developed hepatic steatosis, NASH and fibrosis, conditions associated with ER stress, and insulin resistance. Conversely, the addition of oleic acid to the diet protected against SFA-induced hepatic lipotoxicity.314314. Chen X, Li L, Liu X et al. Oleic acid protects saturated fatty acid mediated lipotoxicity in hepatocytes and rat of non-alcoholic steatohepatitis. Life Sci. 2018 Jun; 203:291-304.SFA or sucrose intake by experimental animals induced SFA accumulation in the liver, ER stress, and apoptosis compared to a PUFA-rich diet.315315. Wang D, Wei Y, Pagliassotti MJ. Saturated fatty acids promote endoplasmic reticulum stress and liver injury in rats with hepatic steatosis. Endocrinology 2006; 147(2):943–51.

A study in humans showed that total fat intake and SFA intake were positively associated with hepatic lipid content.316316. Cheng Y, Zhang K, Chen Y et al. Associations between dietary nutrient intakes and hepatic lipid contents in NAFLD patients quantified by1H-MRS and dual-echo MRI. Nutrients. 2016;8(9). pii: E527.A 7-week randomized double-blind study in healthy individuals revealed that diets rich in palmitic or linoleic acid promoted similar weight gain. However, excess calories from SFAs increased the deposition of liver fat, visceral adipose tissue, and total fat as well as reduced the percentage of lean tissue when compared to a PUFA-rich diet. Additionally, increased body and liver fat correlated positively with elevated plasma concentrations of palmitic acid and inversely with linoleic acid.317317. Rosqvist F, Iggman D, Kullberg J et al. Overfeeding polyunsaturated and saturated fat causes distinct effects on liver and visceral fat accumulation in humans. Diabetes. 2014; 63(7):2356-68.

A recent study showed that an additional consumption of 1000 kcal in the form of SFAs for 3 weeks led to a greater increase in intrahepatic lipid content (55%) when compared to the same extra intake of UFAs or sugars, which elevated hepatic lipid content by 15% and 33%, respectively. SFA intake also induced insulin resistance and increased plasma ceramide concentrations by 49%.318318. Luukkonen PK, Sädevirta S, Zhou Y et al. Saturated fat is more metabolically harmful for the human liver than unsaturated fat or simple sugars. Diabetes Care. 2018; 41(8):1732-9.

9.3. Unsaturated Fatty Acids and Nonalcoholic Steatohepatitis

In the liver, SCD1 is the enzyme primarily responsible for inserting double bonds in saturated chains of fatty acids such as palmitic acid (C16:0) and stearic acid (C18:0), converting them to palmitoleic acid (C16:1) and oleic acid (C18:1), respectively. The aim is to control excess SFA content in the body, either from food or from excess endogenous conversion of palmitic acid derived from de novo lipogenesis. In NAFLD, lipogenic pathways are activated, and desaturation (SCD1) and oxidation pathways are reduced. This is partly due to insulin resistance and mainly due to a local inflammatory process.319319. Cintra DE, Pauli JR, Araújo EP et al. Interleukin-10 is a protective factor against diet-induced insulin resistance in liver. J Hepatol. 2008; 48(4):628-37.Errazuriz et al.320320. Errazuriz I, Dube S, Slama M et al. Randomized controlled trial of a MUFA or fiber-rich diet on hepatic fat in prediabetes. J Clin Endocrinol Metab. 2017; 102(5):1765-74.found that patients with NAFLD had reduced liver fat (assessed by spectroscopic magnetic resonance imaging [MRI]) when they consumed a MUFA-rich diet for 12 weeks (22% of energy) compared to the control group (8% of energy). Such changes occurred even though the diets were isocaloric and the participants had no weight loss at the end of the study.320320. Errazuriz I, Dube S, Slama M et al. Randomized controlled trial of a MUFA or fiber-rich diet on hepatic fat in prediabetes. J Clin Endocrinol Metab. 2017; 102(5):1765-74.

In a randomized study conducted by Bozzetto et al.,321321. Bozzetto L, Prinster A, Annuzzi G et al. Liver fat is reduced by an isoenergetic MUFA diet in a controlled randomized study in type 2 diabetic patients. Diabetes Care. 2012; 35(7):1429-35.patients with T2D were assigned to one of the following interventions: (1) high-MUFA diet; (2) high-carbohydrate/high-fiber/low-glycemic index diet; (3) high-carbohydrate/high-fiber/low-glycemic index diet plus exercise; or (4) high-MUFA diet plus exercise. There was a reduction of up to 30% in hepatic lipid content in patients assigned to the high-MUFA diet, regardless of exercise.321321. Bozzetto L, Prinster A, Annuzzi G et al. Liver fat is reduced by an isoenergetic MUFA diet in a controlled randomized study in type 2 diabetic patients. Diabetes Care. 2012; 35(7):1429-35.The same group of researchers demonstrated, in a subsequent study, that liver fat reduction was due to the activation of hepatic oxidative pathways, based on measurement of β-hydroxybutyrate. Despite having identified an increase in β-oxidation, they found no increase in the ratio of palmitoleic to palmitic acid, which implies that there was no difference in SCD1 activity.322322. Bozzetto L, Costabile G, Luongo D et al. Reduction in liver fat by dietary MUFA in type 2 diabetes is helped by enhanced hepatic fat oxidation. Diabetologia. 2016; 59(12):2697-701.

Together with the lipolytic action promoted by MUFAs, the anti-inflammatory action coordinated by oleic acid may be involved in the potency of the restoration of liver function, as demonstrated by Morari et al.323323. Morari J, Torsoni AS, Anhê GF et al. The role of proliferator-activated receptor γ coactivator-1α in the fatty-acid-dependent transcriptional control of interleukin-10 in hepatic cells of rodents. Metabolism. 2010; 59(2):215-23.In their study, HepG2 cells treated with oleic acid showed increased gene expression and protein content of IL-10, a protein with a potent anti-inflammatory action. Oleic acid activates the protein PGC-1α, which binds to another protein, cMAF. In the form of a dimer, PGC-1α and cMAF migrate to the nucleus and induce exclusive transcription of the IL-10 gene.323323. Morari J, Torsoni AS, Anhê GF et al. The role of proliferator-activated receptor γ coactivator-1α in the fatty-acid-dependent transcriptional control of interleukin-10 in hepatic cells of rodents. Metabolism. 2010; 59(2):215-23.

Similarly, PUFAs have different hepatic metabolic responses. Omega-6 fatty acids (linoleic and arachidonic acids) and ω3 fatty acids (ALA, EPA, and DHA) participate in hepatic metabolism but are primarily intended for constitution of cell membranes, intracellular signaling as second messengers, and other functions, thus being diverted from their use as an energy substrate.324324. Gormaz JG, Rodrigo R, Videla LA et al. Biosynthesis and bioavailability of long-chain polyunsaturated fatty acids in non-alcoholic fatty liver disease. Prog Lipid Res. 2010; 49(4):407-19.In 2007, Yamaguchi et al.325325. Yamaguchi K, Yang L, McCall S et al. Inhibiting triglyceride synthesis improves hepatic steatosis but exacerbates liver damage and fibrosis in obese mice with nonalcoholic steatohepatitis. Hepatology. 2007; 45(6):1366-74.experimentally inhibited hepatic TG synthesis. Despite an improvement in steatosis, liver damage intensified and then progressed to fibrosis and cirrhosis. The study demonstrated that, with an increase in FFAs in the cytoplasm, there was greater ROS oxidation, inducing important inflammation.325325. Yamaguchi K, Yang L, McCall S et al. Inhibiting triglyceride synthesis improves hepatic steatosis but exacerbates liver damage and fibrosis in obese mice with nonalcoholic steatohepatitis. Hepatology. 2007; 45(6):1366-74.

Although some studies suggest an improvement in NAFLD with ω3 fatty acid supplementation,326326. Nogueira MA, Oliveira CP, Ferreira Alves VA et al. Omega-3 polyunsaturated fatty acids in treating non-alcoholic steatohepatitis: A randomized, double-blind, placebo-controlled trial. Clin Nutr. 2016; 35(3):578-86.there are still inconsistencies in the literature regarding its benefits.327327. St-Jules DE, Watters CA, Brunt EM et al. Estimation of fish and ω-3 fatty acid intake in pediatric nonalcoholic fatty liver disease. J Pediatr Gastroenterol Nutr. 2013; 57(5):627-33. , 328328. Dasarathy S, Dasarathy J, Khiyami A et al. Double-blind Randomized Placebo-controlled Clinical Trial of Omega 3 Fatty Acids for the Treatment of Diabetic Patients with Nonalcoholic Steatohepatitis. J Clin Gastroenterol. 2015; 49(2):137-44. In a randomized study of children with NAFLD, daily intake of 1300 mg of ω3 fatty acids for 6 months reduced aspartate aminotransferase and gamma-glutamyl transpeptidase, in addition to increasing serum adiponectin, but these changes were not sufficient to reduce the degree of steatosis on ultrasound.329329. Janczyk W, Lebensztejn D, Wierzbicka-Rucińska A et al. Omega-3 fatty acids therapy in children with nonalcoholic fatty liver disease: a randomized controlled trial. J Pediatr. 2015 Jun; 166(6):1358-63.e1-3.Some of the inconsistencies found in the studies are usually related to the experimental design, the certification of the content of the chosen capsule, and the choice of placebo, among other factors. Tobin et al.330330. Tobin D, Brevik-Andersen M, Qin Y et al. Evaluation of a high concentrate omega-3 for correcting the omega-3 fatty acid nutritional deficiency in non-alcoholic fatty liver disease (CONDIN). Nutrients. 2018; 10(8). pii: E1126.conducted a randomized, double-blind study in which they treated 291 patients with a concentrated ω3 fatty acid capsule (460 mg EPA + 380 mg DHA) or placebo (olive oil) for 24 weeks. MRI-proton density fat fraction assessment showed a significant reduction in hepatic lipid content, similar in both groups, which was attributed to adherence to a healthy dietary pattern.330330. Tobin D, Brevik-Andersen M, Qin Y et al. Evaluation of a high concentrate omega-3 for correcting the omega-3 fatty acid nutritional deficiency in non-alcoholic fatty liver disease (CONDIN). Nutrients. 2018; 10(8). pii: E1126.

Although ω3 fatty acids reduce TG synthesis by blocking SREBP,8383. Hernández-Rodas MC, Valenzuela R, Echeverría F et al. Supplementation with docosahexaenoic acid and extra virgin olive oil prevents liver steatosis induced by a high-fat diet in mice through PPAR-α and Nrf2 upregulation with concomitant SREBP-1c and NF-kB downregulation. Mol Nutr Food Res. 2017;61(12). , 331331. Dossi CG, Tapia GS, Espinosa A et al. Reversal of high-fat diet-induced hepatic steatosis by n-3 LCPUFA: role of PPAR-α and SREBP-1c. J Nutr Biochem. 2014; 25(9):977-84. , 332332. Tajima-Shirasaki N, Ishii KA, Takayama H et al. Eicosapentaenoic acid down-regulates expression of the selenoprotein P gene by inhibiting SREBP-1c protein independently of the AMP-activated protein kinase pathway in H4IIEC3 hepatocytes. J Biol Chem. 2017; 292(26):10791-800. results of clinical trials329329. Janczyk W, Lebensztejn D, Wierzbicka-Rucińska A et al. Omega-3 fatty acids therapy in children with nonalcoholic fatty liver disease: a randomized controlled trial. J Pediatr. 2015 Jun; 166(6):1358-63.e1-3. , 330330. Tobin D, Brevik-Andersen M, Qin Y et al. Evaluation of a high concentrate omega-3 for correcting the omega-3 fatty acid nutritional deficiency in non-alcoholic fatty liver disease (CONDIN). Nutrients. 2018; 10(8). pii: E1126. do not support the recommendation of ω3 fatty acid supplementation in the treatment of NAFLD and NASH, as discussed in a position statement by the American Association for the Study of Liver Diseases.297297. Chalasani N, Younossi Z, Lavine JE et al. The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases. Hepatology. 2018; 67(1):328-57.

9.4. Trans Fatty Acids and Nonalcoholic Steatohepatitis

A high-fat diet enriched with trans fatty acids induced an increase in the expression of transcription factors involved in hepatic lipogenesis (SREBP-1c and PPAR-γ) and reduced MTP, suggesting less ability to export TGs, which led to the development of NASH.308308. Machado RM, Stefano JT, Oliveira CP et al. Intake of trans fatty acids causes nonalcoholic steatohepatitis and reduces adipose tissue fat content. J Nutr. 2010; 140(6):1127-32.A study that evaluated 4242 participants in the NHANES cohort showed a positive association between plasma concentration of trans fatty acids and NAFLD, which was estimated by plasma biomarkers of liver function such as alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, and gamma-glutamyl transferase.333333. Mantovani A. Plasma trans-fatty acid and risk of nonalcoholic fatty liver disease: New data from National Health and Nutrition Examination Survey (NHANES). Int J Cardiol. 2018 Dec; 272:329-330.

Diet composition may influence the development of NAFLD,334334. Musso G, Cassader M, Rosina F et al. Impact of current treatments on liver disease, glucose metabolism and cardiovascular risk in non-alcoholic fatty liver disease (NAFLD): a systematic review and meta-analysis of randomised trials. Diabetologia. 2012; 55(4):885-904.and, within this context, excess SFAs may contribute to intrahepatic lipid accumulation.318318. Luukkonen PK, Sädevirta S, Zhou Y et al. Saturated fat is more metabolically harmful for the human liver than unsaturated fat or simple sugars. Diabetes Care. 2018; 41(8):1732-9.Conversely, healthy dietary patterns rich in UFAs, such as the Mediterranean diet, seem to have beneficial effects, including improved steatosis even if there is no weight loss.335335. Suárez M, Boqué N, Del Bas JM et al. Mediterranean diet and multi-ingredient-based interventions for the management of non-alcoholic fatty liver disease. Nutrients. 2017; 9(10). pii: E1052. , 336336. Baratta F, Pastori D, Polimeni L et al. Adherence to mediterranean diet and non-alcoholic fatty liver disease: effect on insulin resistance. Am J Gastroenterol. 2017; 112(12):1832-9. However, further prospective studies comparing the effect of macronutrients on NAFLD and evaluating pre- and post-treatment histological components are needed.

The treatment of NAFLD consists primarily of weight loss, which is achieved by reducing energy intake by approximately 30%. Losing 3% to 5% of body weight reduces steatosis, and losing 7% to 10% of baseline weight contributes to the improvement of histological components of steatohepatitis and fibrosis.337337. Vilar-Gomez E, Martinez-Perez Y, Calzadilla-Bertot L et al. Weight loss through lifestyle modification significantly reduces features of nonalcoholic steatohepatitis. Gastroenterology. 2015 Aug; 149(2):367-78.e5; quiz e14-5.Physical activity combined with caloric restriction aids weight loss and maintenance.297297. Chalasani N, Younossi Z, Lavine JE et al. The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases. Hepatology. 2018; 67(1):328-57.

Thus, individuals with NAFLD should be instructed to follow a calorie-restricted diet and practice physical activity to lose weight. The adoption of healthy dietary patterns should be encouraged, including a large amount and a varied range of fruits and vegetables, in addition to favoring complex carbohydrates over simple carbohydrates, with increased UFA intake and adequate SFA intake.297297. Chalasani N, Younossi Z, Lavine JE et al. The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases. Hepatology. 2018; 67(1):328-57.

10. Lipid Metabolism in Adipose Tissue

Adipose tissue is composed of adipocytes, preadipocytes, immune cells, fibroblasts, lymph nodes, and nervous tissue. The adipocyte is the only cell that can store fat without compromising its function, which primarily is to promote lipogenesis and lipolysis.338338. Proença AR, Sertié RA, Oliveira AC et al. New concepts in white adipose tissue physiology. Braz J Med Biol Res. 2014;47(3):192-205.Additionally, adipose tissue is able to secrete several bioactive substances such as leptin, cytokines (TNF, IL-6, MCP1, IL-1β), and other adipokines, performing autocrine, paracrine, and endocrine functions.339339. Suganami T, Ogawa Y. Adipose tissue macrophages: their role in adipose tissue remodeling. J Leukoc Biol. 2010; 88(1):33-9.Such actions can be modulated by different fatty acids from the diet.

In response to excess energy and in an attempt to restore tissue homeostasis, the adipose tissue undergoes a remodeling process consisting of adipocyte hypertrophy and hyperplasia and high cytokine secretion, which characterizes them as proinflammatory cytokines.340340. Reilly SM, Saltiel AR. Adapting to obesity with adipose tissue inflammation. Nat Rev Endocrinol. 2017; 13(11):633-43.However, in the long term, secretion of TNF-ɑ, IL-6, iNOS, and MCP1, together with recruitment of inflammatory cells such as neutrophils, T cells, and macrophages, promote inflammation, fibrosis,339339. Suganami T, Ogawa Y. Adipose tissue macrophages: their role in adipose tissue remodeling. J Leukoc Biol. 2010; 88(1):33-9.

340. Reilly SM, Saltiel AR. Adapting to obesity with adipose tissue inflammation. Nat Rev Endocrinol. 2017; 13(11):633-43.
- 341341. Weisberg SP, McCann D, Desai M et al. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest. 2003; 112(12):1796-808. and insulin resistance in adipose tissue,342342. Hotamisligil GS. Inflammation and metabolic disorders. Nature. 2006; 444(7121):860-7.which plays a key role in the metabolic derangements observed in obese patients.343343. Cignarelli A, Genchi VA, Perrini S et al. Insulin and insulin receptors in adipose tissue development. Int J Mol Sci. 2019;20(3). pii: E759.

Cell signaling mediated by TNF-α receptors culminates in NF-kB activation, which increases cytokine secretion and characterizes local inflammation. In this condition, the adipocyte shows increased lipolysis with increased FFA release. SFAs derived from adipocyte lipolysis activate TLR4s in tissue-resident macrophages, intensifying the local inflammatory response and establishing a vicious circle.344344. Suganami T, Nishida J, Ogawa Y. A paracrine loop between adipocytes and macrophages aggravates inflammatory changes: role of free fatty acids and tumor necrosis factor alpha. Arterioscler Thromb Vasc Biol. 2005; 25(10):2062-8.Concomitantly with these actions, there is a gradual polarization of macrophages from the M2 subpopulation (anti-inflammatory action linked to resolution of injury) to the M1 subpopulation (classic activation pathway associated with Th1 response). Thus, there is an intensification of the inflammatory state and induction of insulin resistance in adipose tissue.339339. Suganami T, Ogawa Y. Adipose tissue macrophages: their role in adipose tissue remodeling. J Leukoc Biol. 2010; 88(1):33-9.In obese patients, other factors such as adipose tissue hypoxia, ER stress, and endotoxemia also contribute to the maintenance of inflammation in adipose tissue.

Insulin has an important effect on adipose tissue, as it inhibits lipolysis and stimulates lipogenesis and glucose and FFA uptake. The activation of inflammatory pathways antagonizes the action of insulin by inducing resistance to the hormone and favors the appearance of diseases associated with cardiometabolic risk.343343. Cignarelli A, Genchi VA, Perrini S et al. Insulin and insulin receptors in adipose tissue development. Int J Mol Sci. 2019;20(3). pii: E759.

TGs from the diet are packaged into chylomicrons and hydrolyzed by the action of LPL,343343. Cignarelli A, Genchi VA, Perrini S et al. Insulin and insulin receptors in adipose tissue development. Int J Mol Sci. 2019;20(3). pii: E759.releasing FFAs, which are then directed to adipose tissue and to a lesser extent to the muscle.345345. Savonen R, Hiden M, Hultin M et al. The tissue distribution of lipoprotein lipase determines where chylomicrons bind. J Lipid Res. 2015; 56(3):588-98.Thus, the type of fatty acid in adipose tissue has a strong correlation with the fatty acid in the diet.

10.1. Saturated Fatty Acids and Adipose Tissue Metabolism

An in vitro study showed that preincubation of adipocytes with palmitic acid induced cell hypertrophy with a consequent increase in MCP1 secretion and hydroperoxide concentration, a marker of oxidative stress.345345. Savonen R, Hiden M, Hultin M et al. The tissue distribution of lipoprotein lipase determines where chylomicrons bind. J Lipid Res. 2015; 56(3):588-98.These effects were not observed with oleic acid.345345. Savonen R, Hiden M, Hultin M et al. The tissue distribution of lipoprotein lipase determines where chylomicrons bind. J Lipid Res. 2015; 56(3):588-98. , 346346. Takahashi K, Yamaguchi S, Shimoyama T et al. JNK- and IkappaB-dependent pathways regulate MCP-1 but not adiponectin release from artificially hypertrophied 3T3-L1 adipocytes preloaded with palmitate in vitro. Am J Physiol Endocrinol Metab. 2008; 294(5):E898-909. In another study, palmitic acid activated NF-kB and increased the expression of proinflammatory cytokines in 3T3-L1 adipocytes.347347. Ajuwon KM, Spurlock ME. Palmitate activates the NF-kappaB transcription factor and induces IL-6 and TNFalpha expression in 3T3-L1 adipocytes. J Nutr. 2005; 135(8):1841–6.In experimental animals, a high-fat diet rich in lauric acid induced the activation of proinflammatory cytokines (TNF-α, IL-6, MCP1, IL-1β, IFNγ) and activated serine kinases such as IKKβ and JNK in adipose tissue, with a reduction in AMPK phosphorylation.348348. Lee JH, Zhang Y, Zhao Z et al. Intracellular ATP in balance of pro- and anti-inflammatory cytokines in adipose tissue with and without tissue expansion. Int J Obes (Lond). 2017; 41(4):645-51.Conversely, it increased the production of cytokines with anti-inflammatory action in an attempt to rescue tissue homeostasis.348348. Lee JH, Zhang Y, Zhao Z et al. Intracellular ATP in balance of pro- and anti-inflammatory cytokines in adipose tissue with and without tissue expansion. Int J Obes (Lond). 2017; 41(4):645-51.

In animal models, consumption of a high-fat diet rich in palmitic acid led to increased dendritic cell infiltrate in adipose tissue, together with the development of insulin resistance. In dendritic cells, palmitic acid induced increased expression of maturation markers such as CD40, CD80, MHCII, and TLR4. An increased expression of caspase-1 and IL-1β genes suggests parallel activation of the inflammasome pathway, another intracellular structure involved in the control of inflammatory tone.237237. Reynolds CM, McGillicuddy FC, Harford KA et al. Dietary saturated fatty acids prime the NLRP3 inflammasome via TLR4 in dendritic cells-implications for diet-induced insulin resistance. Mol Nutr Food Res. 2012; 56(8):1212-22.

A subsequent study conducted by the same research group showed that a SFA-rich diet induced insulin resistance, reduced glucose uptake, and increased plasma insulin concentrations. Moreover, there was a reduction in the expression of IRS1 and glucose transporter type 4 in adipose tissue, as well as tyrosine phosphorylation of IRS1 and AKT. These effects were not observed in the groups undergoing the MUFA-rich diet.349349. Finucane OM, Lyons CL, Murphy AM et al. Monounsaturated fatty acid-enriched high-fat diets impede adipose NLRP3 inflammasome-mediated IL-1β secretion and insulin resistance despite obesity. Diabetes. 2015; 64(6):2116-28.

Kolak et al.350350. Kolak M, Westerbacka J, Velagapudi VR et al. Adipose tissue inflammation and increased ceramide content characterize subjects with high liver fat content independent of obesity. Diabetes. 2007; 56(8):1960-8.found that an increase in macrophage infiltrate, MCP1 and PAI1 expression, and ceramide accumulation occurred in subcutaneous adipose tissue regardless of BMI. In addition, these changes positively correlated with hepatic lipid accumulation.

A cross-sectional study that included 484 participants in Japan showed that SFA consumption (assessed by fatty acid concentration in plasma phospholipids) correlated with a reduction in adiponectin and an increase in resistin and visfatin, which are adipokines related to insulin resistance and adipogenesis.351351. Kurotani K, Sato M, Yasuda K et al. Even- and odd-chain saturated fatty acids in serum phospholipids are differentially associated with adipokines. PLoS One. 2017; 12(5):e0178192.

A study of overweight individuals that evaluated the additional consumption of 1000 kcal/day in SFAs (coconut oil and butter), UFAs (olive oil and nuts), or sugars showed that SFAs induced insulin resistance and increased the expression of genes related to inflammatory pathways in adipose tissue.318318. Luukkonen PK, Sädevirta S, Zhou Y et al. Saturated fat is more metabolically harmful for the human liver than unsaturated fat or simple sugars. Diabetes Care. 2018; 41(8):1732-9.

10.2. Unsaturated Fatty Acids and Adipose Tissue Metabolism

Adipose tissue stores SFAs more efficiently; however, if there is a high proportion of UFAs in the diet, lipid deposition on adipose tissue may follow the same dietary profile.352352. Cintra DE, Costa AV, Peluzio Mdo C et al. Lipid profile of rats fed high-fat diets based on flaxseed, peanut, trout, or chicken skin. Nutrition. 2006; 22(2):197-205.Because of the difficulty in investigating tissue dispersion profile of fatty acids obtained from food in humans, most of the studies are conducted in animals.353353. Camell C, Smith CW. Dietary oleic acid increases m2 macrophages in the mesenteric adipose tissue. PLoS One. 2013; 8(9):e75147.Providing a high-fat diet to mice for only 3 days was shown to increase the amounts of palmitic and oleic acid in adipose tissue, with oleic acid being deposited preferably in the mesenteric adipose tissue.

The study also showed that only oleic acid was able to change the inflammatory profile of M1 macrophages to the anti-inflammatory M2 profile, both in animal tissue and in adipocyte culture.353353. Camell C, Smith CW. Dietary oleic acid increases m2 macrophages in the mesenteric adipose tissue. PLoS One. 2013; 8(9):e75147.In the LIPIGENE study, 39 patients with cardiometabolic risk assigned to a high-oleic acid diet showed increased expression of genes that control autophagy (Beclin-1 and ATG7) and apoptosis (CASP3 and CASP7) compared to both the low-fat, high-complex carbohydrate group and the high-complex carbohydrate, high-ω3 fatty acid group.354354. Camargo A, Rangel-Zúñiga OA, Alcalá-Díaz J et al. Dietary fat may modulate adipose tissue homeostasis through the processes of autophagy and apoptosis. Eur J Nutr. 2017; 56(4):1621-8.

Several studies have demonstrated the correlation between arachidonic acid content in adipose tissue and AMI.355355. Lang PD, Degott M, Heuck CC et al. Fatty acid composition of adipose tissue, blood lipids, and glucose tolerance in patients with different degrees of angiographically documented coronary arteriosclerosis. Res Exp Med (Berl). 1982; 180(2):161-8.

356. Wood DA, Riemersma RA, Butler S et al. Linoleic and eicosapentaenoic acids in adipose tissue and platelets and risk of coronary heart disease. Lancet. 1987; 1(8526):177-83.

357. Kark JD, Kaufmann NA, Binka F et al. Adipose tissue n-6 fatty acids and acute myocardial infarction in a population consuming a diet high in polyunsaturated fatty acids. Am J Clin Nutr. 2003; 77(4):796-802.
- 358358. Ba Baylin A, Campos H. Arachidonic acid in adipose tissue is associated with nonfatal acute myocardial infarction in the central valley of Costa Rica. J Nutr. 2004; 134(11):3095-9. A case-cohort study showed a strong correlation (39% of participants) between arachidonic acid content in adipose tissue and AMI.359359. Nielsen MS, Schmidt EB, Stegger J et al. Adipose tissue arachidonic acid content is associated with the risk of myocardial infarction: A Danish case-cohort study. Atherosclerosis. 2013; 227(2):386-90.This is explained by the rapid release of arachidonic acid by the adipocyte, which is a substrate for the synthesis of proinflammatory and prothrombotic eicosanoids, favoring inflammation and destabilization of the atherosclerotic plaque. In addition, this fatty acid has been associated with insulin resistance and may increase cardiovascular risk.359359. Nielsen MS, Schmidt EB, Stegger J et al. Adipose tissue arachidonic acid content is associated with the risk of myocardial infarction: A Danish case-cohort study. Atherosclerosis. 2013; 227(2):386-90.

The known anti-inflammatory potential of ω3 fatty acids seems to positively interfere with the control of tissue inflammation in patients, but more robust evidence is still needed. Spencer et al.360360. Spencer M, Finlin BS, Unal R et al. Omega-3 fatty acids reduce adipose tissue macrophages in human subjects with insulin resistance. Diabetes. 2013; 62(5):1709-17.treated insulin-resistant but nondiabetic patients with 4 g of ω3 fatty acid (ethyl ester) for 12 weeks and observed a significant reduction in MCP1, and thus macrophages, in adipose tissue but not in the muscle. These phenomena were not followed by a reduction in plasma cytokine concentration, insulin sensitivity, or adiponectin. In a coculture experiment of adipocytes and macrophages from the same participants, the adipocytes of patients who consumed ω3 fatty acids had reduced MCP1 content even in the presence of macrophages.360360. Spencer M, Finlin BS, Unal R et al. Omega-3 fatty acids reduce adipose tissue macrophages in human subjects with insulin resistance. Diabetes. 2013; 62(5):1709-17.In a randomized, double-blind controlled study, overweight and obese pregnant women were supplemented with 2 g of ω3 fatty acid (EPA + DHA) twice a day, from gestational week 10 to birth. Plasma concentration of CRP decreased significantly, followed by reduced TLR4 in adipose tissue and decreased gene expression of TNF, IL-6, and IL-8 in placental tissue.361361. Haghiac M, Yang XH, Presley L et al. Dietary omega-3 fatty acid supplementation reduces inflammation in obese pregnant women: a randomized double-blind controlled clinical trial. PLoS One. 2015; 10(9):e0137309.

Difficulties in the development of general recommendations for fatty acid intake in patients with diseases are due to a wide variation in experimental protocols, including different types of food, duration of diets, conflicts of interest of the study authors, and the quality of scientific information, among others.

In a double-blind, placebo-controlled study, insulin-resistant patients were given a daily supplementation of 3.9 g of ω3 fatty acids (EPA + DHA) for 6 months and underwent adipose tissue biopsy before and after the intervention. No benefit associated with tissue metabolism was observed.362362. Hames KC, Morgan-Bathke M, Harteneck DA et al. Very-long-chain ω -3 fatty acid supplements and adipose tissue functions: a randomized controlled trial. Am J Clin Nutr. 2017; 105(6):1552-8.However, in a study of human adipocytes, EPA induced an increase in the expression of genes involved in adipocyte “beiging”. Proteins involved in mitochondrial biogenesis, such as uncoupling protein 1 and carnitine palmitoyltransferase 1, were stimulated. The same study showed, however, that arachidonic acid reduced mitochondrial respiration and then energy expenditure.363363. Fleckenstein-Elsen M, Dinnies D, Jelenik T et al. Eicosapentaenoic acid and arachidonic acid differentially regulate adipogenesis, acquisition of a brite phenotype and mitochondrial function in primary human adipocytes. Mol Nutr Food Res. 2016; 60(9):2065-75.Finally, considering the evidence found to consolidate the decision-making process regarding ω3 fatty acids and their relationship with adipose tissue function, Iturari et al.364364. Itariu BK, Zeyda M, Hochbrugger EE et al. Long-chain n-3 PUFAs reduce adipose tissue and systemic inflammation in severely obese nondiabetic patients: a randomized controlled trial. Am J Clin Nutr. 2012; 96(5):1137-49. , 363363. Fleckenstein-Elsen M, Dinnies D, Jelenik T et al. Eicosapentaenoic acid and arachidonic acid differentially regulate adipogenesis, acquisition of a brite phenotype and mitochondrial function in primary human adipocytes. Mol Nutr Food Res. 2016; 60(9):2065-75. treated 55 obese, nondiabetic patients eligible for bariatric surgery with 3.3 g of ω3 fatty acids (EPA + DHA) for 8 weeks. There was a significant reduction in subcutaneous adipose tissue, content of chemokines CCL2 and CCL3, IL-6, hypoxia-inducible factor 1-alpha and transforming growth factor-beta, and CD40, as well as an increase in adiponectin. No changes induced by ω3 fatty acid consumption in visceral adipose tissue were observed in the experimental group compared to the placebo group.

Despite the potential metabolic benefits from ω3 fatty acid consumption, there is no consensus on its relevance for the treatment of dysmetabolism regarding adipose tissue function. Conversely, there is a greater body of evidence supporting incremental metabolic benefits of MUFAs for conditions associated with dysmetabolism.

11. Food

11.1. Coconut Oil

Coconut oil is composed almost entirely (92%) of SFAs, of which lauric acid accounts for approximately 50%, followed by myristic acid (16%), palmitic acid (8%), and finally caprylic, capric, and stearic acids. Regarding essential fatty acid concentrations, coconut oil has a low concentration of linoleic acid (18:2) and no linolenic acid (18:3).4343. Orsavova J, Misurcova L, Ambrozova JV et al. Fatty acids composition of vegetable oils and its contribution to dietary energy intake and dependence of cardiovascular mortality on dietary intake of fatty acids. Int J Mol Sci. 2015; 16(6):12871-90. , 365365. Eyres L, Eyres MF, Chisholm A et al. Coconut oil consumption and cardiovascular risk factors in humans. Nutr Rev. 2016; 74(4):267-80.

The largest coconut oil producers are the Philippines, Indonesia, and India, extracting two different types of oil: one is refined, bleached, and deodorized, and the other is virgin, cold-pressed, with no refining processes.366366. Wallace TC. Health effects of coconut oil-a narrative review of current evidence. J Am Coll Nutr. 2019; 38(2):97-107.Coconut oil consumption has grown significantly in recent years, and this is partly due to the fact that its properties have been erroneously associated with those of medium-chain triglycerides, formed mainly by caprylic acid (8:0) and capric acid (10:0),367367. Bach A, Babayan V. Medium-chain triglycerides: an update. Am J Clin Nutr. 1982; 36(5):950-62.which are absorbed bound to albumin and reach the liver via portal system, with no consequent increase in TGs. Lauric acid, the main fatty acid in coconut oil, is largely transported by the lymphatic system after being absorbed,3838. McDonald GB, Saunders DR, Weidman M et al. Portal venous transport of long-chain fatty acids absorbed from rat intestine. Am J Physiol. 1980; 239(3):G141-50.and its presence in chylomicrons is dose-dependent.3838. McDonald GB, Saunders DR, Weidman M et al. Portal venous transport of long-chain fatty acids absorbed from rat intestine. Am J Physiol. 1980; 239(3):G141-50.

Beneficial associations regarding coconut oil consumption possibly stem from a study conducted on people from Pukapuka and Tokelau, two Polynesian islands that exhibit low incidence of CVD. The typical diet of this population is rich in saturated fat, and coconut is the main source of fat and energy; protein is obtained mainly from fish, and carbohydrate is obtained from native fruits such as breadfruit. In addition, the diet is high in fiber and low in sucrose and processed foods, because of the limited access to these foods.368368. Prior IA, Davidson F, Salmond CE et al. Cholesterol, coconuts, and diet on Polynesian atolls: a natural experiment: the Pukapuka and Tokelau Island studies. Am J Clin Nutr.1981; 34(8):1552-61.This situation has changed in recent decades, possibly because of the migration to Western dietary habits, even though coconut oil consumption was maintained. In 2010, about 40% of the Polynesian population was diagnosed with chronic diseases (CVD, T2D, and hypertension), which were responsible for three-quarters of deaths in the archipelago.369369. . Pacific islanders pay heavy price for abandoning traditional diet. Bull World Health Organ. 2010; 88(7):484-5.

Coconut oil is able to increase plasma concentrations of TC and LDLc compared to other fats such as olive oil370370. Voon PT, Ng TK, Lee VK et al. Diets high in palmitic acid (16:0), lauric and myristic acids (12:0 + 14:0), or oleic acid (18:1) do not alter postprandial or fasting plasma homocysteine and inflammatory markers in healthy Malaysian adults. Am J Clin Nutr. 2011; 94(6):1451-7.and safflower oil.371371. Cox C, Sutherland W, Mann J et al. Effects of dietary coconut oil, butter and safflower oil on plasma lipids, lipoproteins and lathosterol levels. Eur J Clin Nutr. 1998; 52(9):650-4.A study in humans showed that lauric acid elevates TC and LDLc, compared to a MUFA-rich diet, but less markedly than palmitic acid.372372. Denke MA, Grundy SM. Comparison of effects of lauric acid and palmitic acid on plasma lipids and lipoproteins. Am J Clin Nutr.1992; 56(5):895-8. , 373373. Mendis S, Kumarasunderam R. The effect of daily consumption of coconut fat and soya-bean fat on plasma lipids and lipoproteins of young normolipidaemic men. Br J Clin Nutr. 1990; 63(3):547-52. Mendis et al.373373. Mendis S, Kumarasunderam R. The effect of daily consumption of coconut fat and soya-bean fat on plasma lipids and lipoproteins of young normolipidaemic men. Br J Clin Nutr. 1990; 63(3):547-52.found that the isocaloric replacement of coconut oil, typically found in the diet of Sri Lankan people, with soybean oil rich in PUFAs reduced the plasma concentrations of TC, LDLc, and TG in normolipidemic individuals. The same result was obtained with corn oil in dyslipidemic individuals.219219. Maki KC, Hasse W, Dicklin MR et al. Corn oil lowers plasma cholesterol compared with coconut oil in adults with above-desirable levels of cholesterol in a randomized crossover trial. J Nutr. 2018; 148(10):1556-63.

Furthermore, studies showing increased HDLc concentrations with coconut oil intake have shown a concomitant increase in LDLc, which is known to elevate cardiovascular risk.374374. Feranil AB, Duazo PL, Kuzawa CW et al. Coconut oil is associated with a beneficial lipid profile in pre-menopausal women in the Philippines. Asia Pac J Clin Nutr. 2011; 20(2):190-5.

SFAs are known to activate inflammatory signaling pathways, as well as ER stress, autophagy, and apoptosis, via activation of TLRs linked to the innate immune response.375375. Velloso LA, Folli F, Saad MJ. TLR4 at the crossroads of nutrients, gut microbiota, and metabolic inflammation. Endocr Rev. 2015; 36(3):245-71.TLRs recognize pathogen-associated molecular patterns such as LPS, found in the cell wall of gram-negative bacteria, and then alert the immune system. When activated, TLRs trigger signaling that culminates in the transcription and secretion of proinflammatory cytokines.375375. Velloso LA, Folli F, Saad MJ. TLR4 at the crossroads of nutrients, gut microbiota, and metabolic inflammation. Endocr Rev. 2015; 36(3):245-71.

Lauric acid, among all SFAs, has the greatest inflammatory potential.241241. Lee JY, Sohn KH, Rhee SH et al. Saturated fatty acids, but not unsaturated fatty acids, induce the expression of cyclooxygenase-2 mediated through Toll-like receptor 4. J Biol Chem. 2001; 276(20):16683-9.An in vitro study in macrophages showed that lauric acid induced NF-κB activation, leading to increased expression of cyclooxygenase-2 via activation of TLRs 2 and 4.376376. Lee JY, Ye J, Gao Z et al. Reciprocal modulation of Toll-like receptor-4 signaling pathways involving MyD88 and phosphatidylinositol 3-kinase/AKT by saturated and polyunsaturated fatty acids. J Biol Chem. 2003; 278(39):37041-51.The ability of lauric acid to activate inflammatory pathways by activating TLR4, leading to inflammatory cytokine secretion and T-cell activation, has already been described in different cell types.241241. Lee JY, Sohn KH, Rhee SH et al. Saturated fatty acids, but not unsaturated fatty acids, induce the expression of cyclooxygenase-2 mediated through Toll-like receptor 4. J Biol Chem. 2001; 276(20):16683-9. , 377377. Weatherill AR, Lee JY, Zhao L et al. Saturated and polyunsaturated fatty acids reciprocally modulate dendritic cell functions mediated through TLR4. J Immunol. 2005; 174(9):5390-7.

A study that compared the effect of consuming coconut, palm, or olive oil for 5 weeks on inflammatory parameters of normocholesterolemic individuals found no difference in plasma concentrations of homocysteine and inflammatory markers such as TNF-α, IL-1β, IL-6, INF-γ, and IL-8. However, in that study, the standard deviation was excessively high and may have masked differences in inflammatory profile.370370. Voon PT, Ng TK, Lee VK et al. Diets high in palmitic acid (16:0), lauric and myristic acids (12:0 + 14:0), or oleic acid (18:1) do not alter postprandial or fasting plasma homocysteine and inflammatory markers in healthy Malaysian adults. Am J Clin Nutr. 2011; 94(6):1451-7.

Valente et al.378378. Valente FX, Cândido FG, Lopes LL et al. Effects of coconut oil consumption on energy metabolism, cardiometabolic risk markers, and appetitive responses in women with excess body fat. Eur J Nutr. 2017; 57(4):1627-37.evaluated the acute effect of a diet rich in coconut oil compared to olive oil in 15 overweight women and found no difference regarding energy metabolism and lipid oxidation.

Regarding the antioxidant properties attributed to polyphenols found in virgin coconut oil, studies are still preliminary and were conducted mostly in experimental animals, thus their findings cannot be translated into humans.

To date, there are no randomized controlled studies and epidemiological studies evaluating the effect of coconut oil on lipid profile, inflammatory profile, and cardiovascular outcome. Thus, there is no evidence to indicate coconut oil as a substitute for UFA-rich vegetable oils.

11.2. Palm Oil

Palm oil, together with interesterified fats, has been widely used by the industry as a substitute for trans fat in food. Despite being a vegetable oil, palm oil is composed of SFAs (45% palmitic acid and 5% stearic acid) and UFAs (40% oleic acid and 10% linoleic acid). Thus, an increase in direct consumption of palm oil, or indirect consumption via processed foods, will contribute to a greater SFA intake, which elevates cardiovascular risk.

In humans, a palm oil-rich diet increased plasma concentrations of TC and LDLc compared to consumption of high-UFA vegetable oil.379379. Karupaiah T, Chuah KA, Chinna K et al. Comparing effects of soybean oil- and palm olein-based mayonnaise consumption on the plasma lipid and lipoprotein profiles in human subjects: a double-blind randomized controlled trial with cross-over design. Lipids Health Dis. 2016.17;15(1):131.A meta-analysis of intervention studies found that, compared to vegetable oils with low SFA concentrations such as canola, soybean, and olive oil, palm oil increased the concentrations of TC, LDLc, and, to a modest extent, HDLc, which is consistent with the effect of SFAs on lipoprotein profile. Compared to trans fat, the increase in HDLc was more pronounced, as trans fat intake reduces its concentrations.380380. Sun Y, Neelakantan N, Wu Y et al. Palm Oil Consumption Increases LDL cholesterol compared with vegetable oils low in saturated fat in a meta-analysis of clinical trials. J Nutr. 2015; 145(7):1549-58.Conversely, palm oil seems to have similar effects to animal fat on plasma lipids.380380. Sun Y, Neelakantan N, Wu Y et al. Palm Oil Consumption Increases LDL cholesterol compared with vegetable oils low in saturated fat in a meta-analysis of clinical trials. J Nutr. 2015; 145(7):1549-58. , 381381. Tholstrup T, Hjerpsted J, Raff M. Palm olein increases plasma cholesterol moderately compared with olive oil in healthy individuals. Am J Clin Nutr. 2011; 94(6):1426-32.

Palm oil consumption should be kept within the recommended SFA intake range. Despite being a vegetable oil, palm oil is very rich in palmitic acid and thus seems to act similarly to animal fats.

11.3. Chocolate

Chocolate is obtained from the cocoa bean, which comes mainly from countries in South America and the west coast of Africa. In addition to cocoa, cocoa butter, sugar, milk, and lecithin, other ingredients such as nuts, cereals, and fruits may be incorporated into the manufacture of chocolate, characterizing it as a high-energy density product rich in carbohydrates and fats. Chocolate also has polyphenols and minerals such as potassium, magnesium, iron, and zinc. Approximately 63% of cocoa fat is composed of stearic (34%) and palmitic (27%) acids. The remaining 37% are in the form of MUFAs (33.5%) and PUFAs (3.5%).382382. Torres-Moreno M, Torrescasana E, Salas-Salvadó J et al. Nutritional composition and fatty acids profile in cocoa beans and chocolates with different geographical origin and processing conditions. Food Chem. 2015; 166:125-32.

Because it is rich in stearic acid, cocoa fat has a neutral effect on cholesterolemia. Studies that investigated food consumption in humans show that, compared to palmitic acid, stearic acid reduced plasma concentrations of TC and LDLc in a similar way to oleic acid. In addition, stearic acid increased oleic acid concentrations in plasma CE and TG,383383. Bonanome A, Grundy SM. Effect of dietary stearic acid on plasma cholesterol and lipoprotein levels. N Engl J Med. 1988; 318(19):1244-8.which is explained by the fact that stearic acid is rapidly converted to oleic acid in the liver by the action of SCD1.4848. Grundy SM. Influence of stearic acid on cholesterol metabolism relative to other long-chain fatty acids. Am J Clin Nutr. 1994; 60(6 Suppl):986S-90S.More recent data from the EPIC study showed a positive association between stearic acid concentrations in plasma phospholipids and risk of both coronary heart disease108108. Khaw KT, Friesen MD, Riboli E et al. Plasma phospholipid fatty acid concentration and incident coronary heart disease in men and women: the EPIC-Norfolk prospective study. PLoS Med. 2012; 9(7):e1001255.and T2D.1414. Forouhi NG, Koulman A, Sharp SJ et al. Differences in the prospective association between individual plasma phospholipid saturated fatty acids and incident type 2 diabetes: the EPIC-InterAct case-cohort study. Lancet Diabetes Endocrinol. 2014; 2(10):810-8.However, it is important to note that stearic acid is also endogenously produced by de novo lipogenesis.

Stearic acid intake appears to have a neutral effect on cholesterolemia; however, it must be taken into account that chocolate is also a source of calories and simple sugars, which may contribute to weight gain and increased cardiovascular risk.

11.4. Butter

Butter derives from the cream obtained from milk that was skimmed; therefore, its fat comes exclusively from dairy fat. In a portion of butter, about 51.5% of fatty acids are SFAs, including palmitic (24%), stearic (10%), myristic (8%), and lauric (2%) acids, while the rest is composed of MUFAs (22%) and PUFAs (1.5%).2525. Universidade Estadual de Campinas – UNICAMP. Tabela brasileira de composição de alimentos – TACO. 4. ed. rev. e ampl. Campinas: UNICAMP/NEPA, 2011. pp. 161. Disponível em: http://www.unicamp.br/nepa/taco/tabela.
http://www.unicamp.br/nepa/taco/tabela...

A randomized study evaluating the impact of butter SFAs compared to isocaloric diets rich in UFAs on cardiometabolic risk showed that butter consumption increased the concentrations of TC, LDLc, and ApoB.384384. Brassard D, Tessier-Grenier M, Allaire J et al. Comparison of the impact of SFAs from cheese and butter on cardiometabolic risk factors: a randomized controlled trial. Am J Clin Nutr. 2017; 105(4):800-9.In a prospective cohort study of more than 26 000 individuals, consumption of butter, together with milk and milk products, was inversely associated with incidence of T2D.385385. Ericson U, Hellstrand S, Brunkwall L et al. Food sources of fat may clarify the inconsistent role of dietary fat intake for incidence of type 2 diabetes. Am J Clin Nutr. 2015; 101(5):1065-80.In two other cohorts followed up for 10 and 20 years, no association was found between butter consumption and CVD.386386. Avalos EE, Barrett-Connor E, Kritz-Silverstein D et al. Is dairy product consumption associated with the incidence of CHD? Public Health Nutr. 2013; 16(11):2055-63. , 387387. de Oliveira Otto MC, Mozaffarian D, Kromhout D et al. Dietary intake of saturated fat by food source and incident cardiovascular disease: the Multi-Ethnic Study of Atherosclerosis. Am J Clin Nutr. 2012; 96(2):397-404. However, it should be noted that in the MESA study cohort,387387. de Oliveira Otto MC, Mozaffarian D, Kromhout D et al. Dietary intake of saturated fat by food source and incident cardiovascular disease: the Multi-Ethnic Study of Atherosclerosis. Am J Clin Nutr. 2012; 96(2):397-404.even in the highest quintile, the median consumption of butter was less than 5 g/day per person.

A systematic review of cohort studies with a high degree of evidence found no association between butter consumption and risk of CVD, CAD, and stroke. Conversely, there was an inverse association with risk of T2D.388388. Pimpin L, Wu JH, Haskelberg H et al. Is butter back? A systematic review and meta-analysis of butter consumption and risk of cardiovascular disease, diabetes, and total mortality. Plos One. 2016; 11(6):e0158118.

The results of the studies should be interpreted with caution, as the actions of SFAs in plasma lipids and cardiovascular health have been well consolidated. The use of butter should be part of a healthy, individualized dietary pattern that considers the added energy value and promotes weight management when required.

11.5. Dairy

Milk and milk products are an important source of calcium and high biological value protein. Conversely, whole-fat dairy consumption may increase the intake of SFAs, especially myristic acid, which has a strong correlation with increased cardiovascular risk. Skim dairy consumption is part of the DASH diet recommendations, a dietary pattern that was originally developed for the treatment of hypertension and, because of its cardiometabolic benefits,389389. Azadbakht L, Fard NR, Karimi M et al. Effects of the Dietary Approaches to Stop Hypertension (DASH) eating plan on cardiovascular risks among type 2 diabetic patients: a randomized crossover clinical trial. Diabetes Care. 2011; 34(1):55-7.is recommended as a healthy dietary pattern for all adults.390390. Buse JB, Ginsberg HN, Bakris GL et al. American Heart Association; American Diabetes Association. Primary prevention of cardiovascular diseases in people with diabetes mellitus: a scientific statement from the American Heart Association and the American Diabetes Association. Circulation. 2007; 115(1):114-26.

More recently, studies have shown that dairy consumption is inversely associated with risk of T2D1414. Forouhi NG, Koulman A, Sharp SJ et al. Differences in the prospective association between individual plasma phospholipid saturated fatty acids and incident type 2 diabetes: the EPIC-InterAct case-cohort study. Lancet Diabetes Endocrinol. 2014; 2(10):810-8. , 391391. Yakoob MY, Shi P, Willett WC et al. Circulating biomarkers of dairy fat and risk of incident diabetes mellitus among men and women in the United States in two large prospective cohorts. Circulation. 2016; 133(17):1645-54. stroke,392392. Yakoob MY, Shi P, Hu FB et al. Circulating biomarkers of dairy fat and risk of incident stroke in U.S. men and women in 2 large prospective cohorts. Am J Clin Nutr 2014; 100(6):1437-47.and CVD.110110. de Oliveira Otto MC, Nettleton JA, Lemaitre RN et al. Biomarkers of dairy fatty acids and risk of cardiovascular disease in the Multi-ethnic Study of Atherosclerosis. J Am Heart Assoc. 2013; 2(4):e000092.In those studies, plasma concentrations of pentadecanoic acid (15:0) and heptadecanoic acid (17:0) were used as markers of dairy consumption, as, because they are not endogenously synthesized, they must be obtained from the diet, and dairy is their main source.

It is important to note that the food matrix is a determining factor in cardiovascular risk, as, in addition to macronutrients, food provides micronutrients and fibers that contribute to a favorable cardiovascular outcome within the context of healthy dietary patterns. In contrast, the inclusion of processed foods rich in simple, refined sugars and additives such as food coloring agents, preservatives, and thickeners, may negatively impact cardiovascular risk. Additionally, the use of lipid-lowering drugs such as statins may mitigate or even mask the effects of SFA consumption on cardiovascular risk.106106. Praagman J, Beulens JW, Alssema M et al. The association between dietary saturated fatty acids and ischemic heart disease depends on the type and source of fatty acid in the European Prospective Investigation into Cancer and Nutrition-Netherlands cohort. Am J Clin Nutr 2016; 103(2):356-65.

11.6. Meat

The most consumed types of meat are beef, chicken, and pork, which are important nutritional sources of high biological value proteins, providing all essential amino acids, vitamins, and minerals. The amount of fat and the distribution of fatty acids will vary according to the source and the type of meat cut. Overall, meats contain mostly MUFAs and SFAs (especially palmitic and stearic acids) and a small amount of PUFAs.2525. Universidade Estadual de Campinas – UNICAMP. Tabela brasileira de composição de alimentos – TACO. 4. ed. rev. e ampl. Campinas: UNICAMP/NEPA, 2011. pp. 161. Disponível em: http://www.unicamp.br/nepa/taco/tabela.
http://www.unicamp.br/nepa/taco/tabela...
, 2828. Almeida JC, Perassolo MS, Camargo JL et al. Fatty acid composition and cholesterol content of beef and chicken meat in Southern Brazil. Rev Bras Cienc Farm. 2006; 42(1):109-17.

A positive association between meat consumption and cardiovascular risk has been observed in some studies110110. de Oliveira Otto MC, Nettleton JA, Lemaitre RN et al. Biomarkers of dairy fatty acids and risk of cardiovascular disease in the Multi-ethnic Study of Atherosclerosis. J Am Heart Assoc. 2013; 2(4):e000092.but not in others.393393. Afshin A, Micha R, Khatibzadeh S et al; 2010 Global Burden of Diseases, Injuries, and Risk Factors Study: NUTRItrition and ChrOnic Diseases Expert Group (NUTRICODE), and Metabolic Risk Factors of ChrOnic Diseases Collaborating Group. The impact of dietary habits and metabolic risk factors on cardiovascular and diabetes mortality in countries of the Middle East and North Africa in 2010: a comparative risk assessment analysis. BMJ Open. 2015; 5(5):e006385.A study of more than 780 individuals found that consumption of red and processed meats correlated with a less healthy dietary pattern but not with CVD and T2D risk markers.394394. Lenighan YM, Nugent AP, Li KF et al. Processed red meat contribution to dietary patterns and the associated cardio-metabolic outcomes. Br J Nutr. 2017; 118(3):222-8.A prospective cohort study of more than 74 thousand individuals showed an association between greater consumption of (processed and unprocessed) meat and increased risk of CVD mortality (such association was found even in individuals with greater consumption of fruits and vegetables).395395. Bellavia A, Stilling F, Wolk A. High red meat intake and all-cause cardiovascular and cancer mortality: is the risk modified by fruit and vegetable intake? Am J Clin Nutr. 2016; 104(4):1137-43.

An increased risk of all-cause and CVD mortality was associated with greater consumption of red and processed meats but not with consumption of unprocessed meats alone in two meta-analyses.396396. O’Sullivan TA, Hafekost K, Mitrou F, Lawrence D. Food sources of saturated fat and the association with mortality: a meta-analysis. Am J Public Health. 2013; 103(9):e31-42. , 397397. Wang X, Lin X, Ouyang YY et al. Red and processed meat consumption and mortality: dose-response meta-analysis of prospective cohort studies. Public Health Nutr. 2016; 19(5):893-905. Processed meats are also rich in sodium and nitrogen compounds such as nitrates, which may contribute to a deleterious effect on cardiovascular risk because of their effects on blood pressure and endothelial function.

It is well established that high consumption of red and processed meats is associated with an increased cardiovascular risk, which is why their intake should be moderate and consistent with the total SFA intake recommended in the diet.

12. Gut Microbiota

High-fat diets, especially those rich in SFAs, are able to change the composition of gut microbiota,398398. de Wit N, Derrien M, Bosch-Vermeulen H et al. Saturated fat stimulates obesity and hepatic steatosis and affects gut microbiota composition by an enhanced overflow of dietary fat to the distal intestine. Am J Physiol Gastrointest Liver Physiol. 2012; 303(5):G589-99.

399. Liu T, Hougen H, Vollmer AC et al. Gut bacteria profiles of Mus musculus at the phylum and family levels are influenced by saturation of dietary fatty acids. Anaerobe. 2012; 18(3):331-7.
- 400400. Devkota S, Wang Y, Musch MW et al. Dietary-fat-induced taurocholic acid promotes pathobiont expansion and colitis in Il10−/− mice. Nature. 2012; 487(7405):104-8. induce decreased bacterial diversity, increased intestinal permeability, metabolic endotoxemia, and low-grade systemic inflammation,401401. Cani PD, Amar J, Iglesias MA et al. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes. 2007; 56(7):1761-72.

402. Cani PD, Bibiloni R, Knauf C et al. Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet–induced obesity and diabetes in mice. Diabetes. 2008; 57(6):1470-81.

403. Pendyala S, Walker JM, Holt PR. A high-fat diet is associated with endotoxemia that originates from the gut. Gastroenterology. 2012; 142(5):1100-1.e2.

404. Laugerette F, Vors C, Peretti N et al. Complex links between dietary lipids, endogenous endotoxins and metabolic inflammation. Biochimie. 2011; 93(1):39-45.

405. Carvalho BM, Saad MJ. Influence of gut microbiota on subclinical inflammation and insulin resistance. Mediators Inflamm. 2013 Jun; 2013:986734.

406. Huang EY, Leone VA, Devkota S et al. Composition of dietary fat source shapes gut microbiota architecture and alters host inflammatory mediators in mouse adipose tissue. JPEN J Parenter Enteral Nutr. 2013; 37(6):746-54.
- 407407. López-Moreno J, García-Carpintero S, Jimenez-Lucena R et al. Effect of dietary lipids on endotoxemia influences postprandial inflammatory response. J Agric Food Chem. 2017; 65(35):7756-63. and influence the development of several chronic diseases such as obesity, diabetes, and atherosclerosis.408408. He C, Shan Y, Song W. Targeting gut microbiota as a possible therapy for diabetes. Nutr Res. 2015; 35(5):361-7.Loss of intestinal epithelium integrity allows LPS from the cell membrane of gram-negative bacteria to translocate into plasma, culminating in metabolic endotoxemia.401401. Cani PD, Amar J, Iglesias MA et al. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes. 2007; 56(7):1761-72. , 403403. Pendyala S, Walker JM, Holt PR. A high-fat diet is associated with endotoxemia that originates from the gut. Gastroenterology. 2012; 142(5):1100-1.e2.

A greater consumption of high-SFA diets has been shown to increase intestinal paracellular permeability by interfering in tight-junction proteins, and thereby plasma concentrations of LPS are elevated.409409. Lam YY, Ha CW, Hoffmann JM et al. Effects of dietary fat profile on gut permeability and microbiota and their relationships with metabolic changes in mice. Obesity (Silver Spring). 2015; 23(7):1429-39. , 410410. Wiest R, Rath HC. Bacterial translocation in the gut. Best Pract Res Clin Gastroenterol. 2003; 17(3):397-425. Changes in intestinal permeability are related to the regulation of tight-junction proteins, a protein complex that maintains cell-cell junctions in the intestinal epithelium, forming a barrier against the passage of macromolecules.411411. Fasano A. Zonulin and its regulation of intestinal barrier function: the biological door to inflammation, autoimmunity, and cancer. Physiol Rev. 2011; 91(1):151-75.

A study in mice found that a high-SFA diet induced greater formation of taurocholic acid, which allowed the expansion of sulfate-reducing bacteria such as Bilophila wadsworthia , an effect that was not observed in a high-PUFA diet. That study shows that changes in the composition of bile acids due to the type of dietary fat may cause dysbiosis, compromising host homeostasis.400400. Devkota S, Wang Y, Musch MW et al. Dietary-fat-induced taurocholic acid promotes pathobiont expansion and colitis in Il10−/− mice. Nature. 2012; 487(7405):104-8.

An increase in intestinal permeability induced by a high-fat diet, consisting mainly of SFAs, leads to changes in gut microbiota and increased inflammatory response, triggered by TLR4 activation by LPS.412412. Kim KA, Gu W, Lee IA et al. High fat diet-induced gut microbiota exacerbates inflammation and obesity in mice via the TLR4 signaling pathway. PLoS One. 2012; 7(10):e47713.Another mechanism may be associated with decreased secretion of the enzyme intestinal alkaline phosphatase by the duodenal brush border, which is responsible for detoxifying LPS, thus protecting against endotoxemia.413413. de La Serre CB, Ellis CL, Lee J et al. Propensity to high-fat diet-induced obesity in rats is associated with changes in the gut microbiota and gut inflammation. Am J Physiol Gastrointest Liver Physiol. 2010; 299(2):G440-8.

An experimental study showed that a high-fat diet, especially when combined with a high-sugar diet, induces dysbiosis and inflammation in the intestinal epithelium and changes the activation of the vagal afferent pathway, actions that may impair the regulation of food intake, contributing to hyperphagia and development of obesity.414414. Paulino G, Barbier de la Serre C, Knotts TA et al. Increased expression of receptors for orexigenic factors in nodose ganglion of diet-induced obese rats. Am J Physiol Endocrinol Metab. 2009; 296(4):E898-903.

12.1. Dietary Patterns and Gut Microbiota

Diet components have an important impact on the profile of gut microbiota. Therefore, different dietary patterns can modulate gut microbiota in distinct ways.

A study that investigated the association of dietary variables with gut microbiota identified 97 nutrients associated with relative abundance data or with presence/absence of microbiomes. The nutrients were divided into four groups: amino acids and choline; carbohydrates; fats; and fibers and vegetables. The study showed that the fat versus fiber groups were antagonistically associated with bacterial abundance,415415. Wu GD, Chen J, Hoffmann C et al. Linking long-term dietary patterns with gut microbial enterotypes. Science. 2011; 334(6052):105-8.i.e., bacteria that were positively associated with fat tended to be negatively associated with fibers. The same pattern of association was seen for the amino acid and protein versus carbohydrate groups and the fat versus carbohydrate groups. In addition, microbial rates that correlated with BMI also correlated with higher consumption of fats and SFAs.415415. Wu GD, Chen J, Hoffmann C et al. Linking long-term dietary patterns with gut microbial enterotypes. Science. 2011; 334(6052):105-8.

A recent randomized study of 217 healthy individuals compared the effect of isocaloric diets containing increasing concentrations of fat (20%, 30%, and 40%) and the same amount of fiber (14 g/day).416416. Wan Y, Wang F, Yuan J et al. Effects of dietary fat on gut microbiota and faecal metabolites, and their relationship with cardiometabolic risk factors: a 6-month randomised controlled-feeding trial. Gut. 2019; 68(8):1417-29.The high-fat diet increased fecal concentrations of palmitic, stearic, and arachidonic acids. The latter was positively associated with increased plasma concentrations of inflammatory mediators such as CRP as well as PGE2 and thromboxane B2, both derived from arachidonic acid. An important result of that study was that, even with adequate amounts of fiber in the diet, a high fat consumption prevented the formation of short-chain fatty acids (SCFAs) by bacteria.416416. Wan Y, Wang F, Yuan J et al. Effects of dietary fat on gut microbiota and faecal metabolites, and their relationship with cardiometabolic risk factors: a 6-month randomised controlled-feeding trial. Gut. 2019; 68(8):1417-29.Additionally, increased fat consumption reduced bacterial diversity.

12.2. Importance of Dietary Pattern in Short-chain Fatty Acid Synthesis

The production of glycoside hydrolases, which are responsible for the breakdown of some saccharides, is very limited in the human body. Conversely, some intestinal bacteria encode enzymes capable of digesting a wide range of polysaccharides, such as fibers.417417. Kaoutari A El, Armougom F, Gordon JI et al. The abundance and variety of carbohydrate-active enzymes in the human gut microbiota. Nat Rev Microbiol. 2013; 11(7):497-504.The fermentation of soluble fibers promotes the formation of SCFAs, especially propionate (C3), acetate (C4), and butyrate (C5), which, in addition to serving as an energy substrate for colonocytes, perform systemic actions such as favoring glucose homeostasis.418418. Canfora EE, Jocken JW, Blaak EE. Short-chain fatty acids in control of body weight and insulin sensitivity. Nat Rev Endocrinol. 2015; 11(10):577-91. , 419419. Louis P, Flint HJ. Formation of propionate and butyrate by the human colonic microbiota. Environ Microbiol. 2017;19(1):29-41.

The presence of SCFAs induces secretion of intestinal incretins, such as GLP-1 and PYY, which act on the central nervous system by promoting satiety and reducing food consumption, decreasing gastric emptying time, increasing intestinal transit, in addition to stimulating insulin synthesis and secretion by the pancreas.418418. Canfora EE, Jocken JW, Blaak EE. Short-chain fatty acids in control of body weight and insulin sensitivity. Nat Rev Endocrinol. 2015; 11(10):577-91.

A reduction in fiber consumption may impact the composition of the gut microbiota and the production of SCFAs. A prospective study of 17 obese individuals evaluated the impact of two high-protein/high-fat/low-fiber diets. The results show that both diets decreased fecal production of SCFAs and increased the concentration of branched-chain fatty acids, phenylacetic acid, and nitrogenous compounds, which are detrimental to colonic health.420420. Russell WR, Gratz SW, Duncan SH et al. High-protein, reduced-carbohydrate weight-loss diets promote metabolite profiles likely to be detrimental to colonic health. Am J Clin Nutr. 2011; 93(5):1062-72.

13. Dietary Cholesterol

13.1. Plasma Concentration of Lipids and Lipoproteins

The relationship between dietary cholesterol and plasma TC has been shown to be linear in observational cohort studies.421421. Djousse L, Gaziano JM. Egg consumption in relation to cardiovascular disease and mortality: the Physicians’ Health Study. Am J Clin Nutr. 2008; 87(4):964-9. , 422422. McGill HC, Jr. The relationship of dietary cholesterol to serum cholesterol concentration and to atherosclerosis in man. Am J Clin Nutr. 1979; 32(12 Suppl):2664-702. However, observational studies have limitations such as the presence of confounding variables, which may increase the magnitude of correlations, both positive and negative, and selection biases.423423. Song JW, Chung KC. Observational studies: cohort and case-control studies. Plast Reconstr Surg. 2010; 126(6):2234-42.Furthermore, dietary cholesterol consumption is generally associated with increased consumption of SFAs, which are known to increase LDLc and cardiovascular risk.424424. Hu FB, Manson JE, Willett WC. Types of dietary fat and risk of coronary heart disease: a critical review. J Am Coll Nutr. 2001; 20(1):5-19.

In recent years, there has been an intense discussion about the role of dietary cholesterol in the incidence of atherosclerotic complications. In response to that, the AHA no longer limits egg consumption as a way of protecting against CVDs. Thus, the Dietary Guidelines for Americans withdrew a recommendation for restricting cholesterol intake to no more than 300 mg per day.77. U.S. Department of Health and Human Services and U.S. Department of Agriculture. 2015 – 2020 Dietary Guidelines for Americans. 8th ed Dec, 2015.However, the guidelines suggest that dietary cholesterol remains important and should be considered for developing healthy dietary patterns. They also highlight that dietary cholesterol consumption should be as low as possible, as recommended by the Institute of Medicine.425425. Institute of Medicine. Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids. Washington (DC): The National Academies Press; 2002.As noted, food sources containing high amounts of cholesterol are usually also rich in SFAs, such as fatty meats and high-fat dairy products. Therefore, the recommendation focuses on restricting SFAs to less than 10% per day, which should be sufficient to control dietary cholesterol.77. U.S. Department of Health and Human Services and U.S. Department of Agriculture. 2015 – 2020 Dietary Guidelines for Americans. 8th ed Dec, 2015.

It is worth mentioning that not all people respond the same way to dietary cholesterol consumption, as the response is highly variable depending on genetic and metabolic factors426426. McNamara DJ, Kolb R, Parker TS et al. Heterogeneity of cholesterol homeostasis in man. Response to changes in dietary fat quality and cholesterol quantity. J Clin Invest. 1987; 79(6):1729-39. , 427427. Berger S, Raman G, Vishwanathan R et al. Dietary cholesterol and cardiovascular disease: a systematic review. Am J Clin Nutr. 2015; 102(2):276-94. Lipid profile responses to dietary cholesterol were examined in 19 intervention studies. Cholesterol intake, mainly from eggs, led to an increase in both LDLc and HDLc, resulting in a slight increase in the LDLc/HDLc ratio. However, the analysis of this ratio can be very simplistic, as, while LDLc is an excellent marker of cardiovascular risk and changes in its value show a marked relationship with cardiovascular risk, changes in HDLc do not express possible changes in the functionality of HDL particles, which extends far beyond reverse cholesterol transport.428428. Kosmas CE, Martinez I, Sourlas A et al. High-density lipoprotein (HDL) functionality and its relevance to atherosclerotic cardiovascular disease. Drugs Context. 2018 Mar; 7:212525.

Cholesterol consumption up to 400 mg/day from eggs is not associated with increased plasma TG concentrations in overweight individuals with diabetes or prediabetes.429429. Fuller NR, Caterson ID, Sainsbury A et al. The effect of a high-egg diet on cardiovascular risk factors in people with type 2 diabetes: the Diabetes and Egg (DIABEGG) study-a 3-mo randomized controlled trial. Am J Clin Nutr. 2015; 101(4):705-13.

13.2. Risk of Developing Type 2 Diabetes

Observational and randomized studies have shown conflicting results regarding the association between dietary cholesterol consumption and risk of T2D. A case-control study demonstrated a 2-fold increase in the risk of T2D in individuals who consumed 3 to 4.9 eggs per week and a 3-fold increase in those who consumed more than 5 eggs per week, after adjusting for confounding factors such as BMI, family history of diabetes, smoking, physical activity, and plasma TG concentration.430430. Radzeviciene L, Ostrauskas R. Egg consumption and the risk of type 2 diabetes mellitus: a case-control study. Pub Health Nutr 2012; 15(8):1437-41.An investigation that used data from two prospective randomized studies, Physicians’ Health Study I (1982-2007) and Women’s Health Study (1992-2007), demonstrated that during follow-up (20 years in men and 11.7 years in women) the development of diabetes was higher in those who consumed more than 5 eggs per week in men and more than 7 eggs per week in women, after multivariate adjustments.431431. Djoussé L, Gaziano JM, Buring JE et al. Egg consumption and risk of type 2 diabetes in men and women. Diabetes Care. 2009; 32(2):295-300.However, other studies of populations from different regions have not shown the same association. A prospective study of the Japanese population (Japan Public Health Center-based Prospective Study) with a 5-year follow-up concluded that high intake of dietary cholesterol or eggs was not associated with a higher risk of T2D.432432. Kurotani K, Nanri A, Goto A et al. Cholesterol and egg intakes and the risk of type 2 diabetes: the Japan Public Health Center-based Prospective Study. Br J Nutr. 2014; 112(10):1636-43.Opposite results were observed in the male population of the KuopioI Schaemic Heart Disease Risk Factor Study, which found that a higher egg consumption was associated with a lower risk of T2D in a 19.3-year follow-up.433433. Virtanen JK, Mursu J, Tuomainen TP et al. Egg consumption and risk of incident type 2 diabetes in men: the Kuopio Ischaemic Heart Disease Risk Factor Study. Am J Clin Nutr. 2015; 101(5):1088-96.

In the Jackson Heart Study, in an African American population, a higher prevalence of T2D was observed in those who consumed more eggs (> 5 eggs/week vs < 1 egg/month); however, a prospective analysis showed no association between egg consumption and incidence of T2D.434434. Djoussé L, Petrone AB, Hickson DA et al. Egg consumption and risk of type 2 diabetes among African Americans: The Jackson Heart Study. Clin Nutr. 2016; 35(3):679-84.

In systematic reviews and meta-analyses with healthy individuals, there was also no consensus on the association between egg consumption and increased risk of CVD and T2D.435435. Geiker NRW, Larsen ML, Dyerberg J et al. Egg consumption, cardiovascular diseases and type 2 diabetes. Eur J Clin Nutr. 2018; 72(1):44-56. , 436436. Tran NL, Barraj LM, Heilman JM et al. Egg consumption and cardiovascular disease among diabetic individuals: a systematic review of the literature. Diab Metab Syndr Obes. 2014 Mar; 7:121-37. The results can be explained in part by confounding factors such as SFA intake and dietary energy intake, which favor weight gain and development of metabolic syndrome.437437. Richard C, Cristall L, Fleming E et al. Impact of egg consumption on cardiovascular risk factors in individuals with type 2 diabetes and at risk for developing diabetes: a systematic review of randomized nutritional intervention studies. Can J Diabetes. 2017; 41(4):453-63

13.3. Risk of Cardiovascular Diseases in Type 2 Diabetes

Another issue under discussion is the role of dietary cholesterol in cardiovascular risk in individuals with T2D or metabolic syndrome.

Observational and prospective studies associate egg consumption with a higher risk of CVD in the general population, while others only found association in individuals with T2D.438438. Jang J, Shin MJ, Kim OY et al. Longitudinal association between egg consumption and the risk of cardiovascular disease: interaction with type 2 diabetes mellitus. Nutr Diabetes. 2018; 8(1):20.A meta-analysis concluded that the consumption of > 1 egg per day increased by 1.69 times the risk of developing CVD compared to the consumption of no eggs or < 1 egg per week. However, egg consumption was not associated with mortality.439439. Shin JY, Xun P, Nakamura Y et al. Egg consumption in relation to risk of cardiovascular disease and diabetes: a systematic review and meta-analysis. Am J Clin Nutr. 2013; 98(1):146-59.

A randomized study of individuals with prediabetes or T2D (DIADEGG Study) who were assigned a diet with high (2 eggs/day for 6 days/week) or low (< 2 eggs/week) egg consumption for 3 months concluded that greater consumption of dietary cholesterol did not change plasma concentrations of HDLc, LDLc, and TC. The study also showed that there was no increase in risk factors for CVD in patients with T2D.429429. Fuller NR, Caterson ID, Sainsbury A et al. The effect of a high-egg diet on cardiovascular risk factors in people with type 2 diabetes: the Diabetes and Egg (DIABEGG) study-a 3-mo randomized controlled trial. Am J Clin Nutr. 2015; 101(4):705-13.

In the NHS population, lower consumption of dietary cholesterol (assessed by the intake of eggs and meat) in patients with T2D was associated with healthier quality of life and thus lower risk of CVD. When quality-of-life factors were controlled for, the association between cholesterol consumption and risk of CVD was attenuated, suggesting that the improvement in quality of life is also associated with cardiovascular risk, and not only with dietary cholesterol.440440. Tanasescu M, Cho E, Manson JE et al. Dietary fat and cholesterol and the risk of cardiovascular disease among women with type 2 diabetes. Am J Clin Nutr. 2004; 79(6):999-1005.

Results based on the Framingham Offspring Study population, which was followed up for 20 years, demonstrated no association of dietary cholesterol consumption with fasting lipid profile or risk of CVD in individuals with altered fasting blood glucose or T2D.441441. Baghdasarian S, Lin HP, Pickering RT et al. Dietary Cholesterol Intake Is Not Associated with Risk of Type 2 Diabetes in the Framingham Offspring Study. Nutrients. 2018; 10(6). pii: E665.

An analysis of the prospective PREDIMED study population, which included participants with no previous cardiovascular events who were followed up for an average of 5.8 years, concluded that low or moderate egg consumption did not increase the risk of CVD in individuals either with or without T2D.442442. Díez-Espino J, Basterra-Gortari FJ, Salas-Salvadó J et al; PREDIMED Investigators. Egg consumption and cardiovascular disease according to diabetic status: The PREDIMED study. ClinNutr. 2017; 36(4):1015-21.

Results of prospective randomized and observational studies, as well as systematic reviews and meta-analyses, are inconclusive regarding the association between greater consumption of dietary cholesterol and greater risk of CVD in individuals with T2D because of the high heterogeneity of the populations evaluated and methods used.

13.4. Impact on Cardiovascular Diseases

The available scientific evidence is conflicting regarding the impact of cholesterol intake on cardiovascular risk. Several studies suggest lack of association between dietary cholesterol and CAD or stroke, although there are limitations to be considered in the results.427427. Berger S, Raman G, Vishwanathan R et al. Dietary cholesterol and cardiovascular disease: a systematic review. Am J Clin Nutr. 2015; 102(2):276-94. , 443443. Cheng P, Pan J, Xia J et al. Dietary cholesterol intake and stroke risk: a meta-analysis. Oncotarget. 2018; 9(39):25698-707. , 444444. Larsson SC, Åkesson A, Wolk A. Egg consumption and risk of heart failure, myocardial infarction, and stroke: results from 2 prospective cohorts. Am J Clin Nutr. 2015; 102(5):1007-13. In Asians, the highest quartile of dietary cholesterol consumption did not correlate with increased subclinical atherosclerosis assessed by calcium scoring.445445. Rhee EJ, Ryu S, Lee JY et al. The association between dietary cholesterol intake and subclinical atherosclerosis in Korean adults: The Kangbuk Samsung Health Study. J Clin Lipidol. 2017; 11(2):432-41.e3.In Finns, consumption of more than 400 mg of cholesterol per day was not associated with increased intima-media thickness or incidence of CAD.446446. Virtanen JK, Mursu J, Virtanen HEK et al. Associations of egg and cholesterol intakes with carotid intima-media thickness and risk of incident coronary artery disease according to apolipoprotein E phenotype in men: the Kuopio Ischaemic Heart Disease Risk Factor Study. Am J Clin Nutr. 2016; 103(3):895-901.However, in Americans, adding 300 mg of cholesterol to a baseline diet containing an average of 300 mg of cholesterol per day was associated with a 17% increase in CVD risk.447447. Zhong VW, Van Horn L, Cornelis MC et al. Associations of dietary cholesterol or egg consumption with incident cardiovascular disease and mortality. JAMA. 2019; 321(11):1081-95.

Because high cholesterol consumption may be associated with an increased risk of developing CVD, and such risk may be dose-dependent, monitoring cholesterol intake is recommended.447447. Zhong VW, Van Horn L, Cornelis MC et al. Associations of dietary cholesterol or egg consumption with incident cardiovascular disease and mortality. JAMA. 2019; 321(11):1081-95.

14. EGG

Egg is a low-SFA source of dietary cholesterol with high nutrient density and low cost. A chicken egg (50 g) contains high biological value protein (7.5 g), SFAs (1.6 g), MUFAs (1.8 g), PUFAs (0.9 g), and cholesterol (approximately 200 mg). Egg yolk is also rich in choline (147 mg), an essential nutrient for liver and muscle functions.2525. Universidade Estadual de Campinas – UNICAMP. Tabela brasileira de composição de alimentos – TACO. 4. ed. rev. e ampl. Campinas: UNICAMP/NEPA, 2011. pp. 161. Disponível em: http://www.unicamp.br/nepa/taco/tabela.
http://www.unicamp.br/nepa/taco/tabela...
, 448448. Clayton ZS, Fusco E, Kern M. Egg consumption and heart health: A review. Nutrition. 2017 May; 37:79-85.

The impact of egg consumption on lipid profile is quite variable.449449. Blesso CN, Fernandez ML. Dietary cholesterol, serum lipids, and heart disease: Are eggs working for or against you? Nutrients. 2018; 10(4). pii: E426.In healthy adolescents, the consumption of more than 3 eggs per week is not associated with changes in lipid profile.450450. Mott MM, McCrory MA, Bandini LG et al. Egg intake has no adverse association with blood lipids or glucose in adolescent girls. J Am Coll Nutr. 2019; 38(2):119-24.Similarly, in normolipidemic and physically active adults, the consumption of 2 eggs per day did not change plasma concentrations of lipoproteins after 12 weeks of study.451451. Clayton ZS, Scholar KR, Shelechi M et al. Influence of resistance training combined with daily consumption of an egg-based or bagel-based breakfast on risk factors for chronic diseases in healthy untrained individuals. J Am Coll Nutr. 2015; 34(2):113-9.Conversely, a meta-analysis of 28 studies evaluating the consumption of from 5 eggs per week to 3 eggs per day showed that egg consumption in hyper-responsive individuals increases the concentration of TC by 5.60 mg/dL (95% CI: 3.11-8.09; P < 0.0001), LDLc by 5.55 mg/dL (95% CI: 3.14-7.69; P < 0.0001), and HDLc by 2.13 mg/dL (95% CI: 1.10-3.16; P < 0.0001), having a neutral effect on TG concentration compared to no egg consumption.452452. Rouhani MH, Rashidi-Pourfard N, Salehi-Abargouei A et al. Effects of Egg Consumption on Blood Lipids: A Systematic Review and Meta-Analysis of Randomized Clinical Trials. J Am Coll Nutr. 2018; 37(2):99-110.Nonetheless, there is evidence that egg consumption is associated with larger LDLc particles, which are less susceptible to oxidation and penetration into the endothelium.449449. Blesso CN, Fernandez ML. Dietary cholesterol, serum lipids, and heart disease: Are eggs working for or against you? Nutrients. 2018; 10(4). pii: E426.

Findings on the impact of egg consumption on CVD risk, remain conflicting. A meta-analysis assessing the impact of consuming 1 egg per day versus < 2 eggs per week on the risk of CAD and stroke found no association between egg consumption and coronary risk in 7 studies of low heterogeneity.453453. Alexander DD, Miller PE, Vargas AJ et al. Meta-analysis of Egg Consumption and Risk of Coronary Heart Disease and Stroke. J Am Coll Nutr. 2016; 35(8):704-16.Conversely, there was a 12% reduction in the risk of stroke with increased egg consumption and no dose-response relationship in the risk trend for stroke with increased egg consumption.453453. Alexander DD, Miller PE, Vargas AJ et al. Meta-analysis of Egg Consumption and Risk of Coronary Heart Disease and Stroke. J Am Coll Nutr. 2016; 35(8):704-16.

In a cohort study of the Chinese population, high egg consumption (7 or more eggs per week) compared to low egg consumption (< 1 egg per week) was not associated with cardiovascular mortality, CAD, or stroke.454454. Xu L, Lam TH, Qiang C et al. Egg consumption and the risk of cardiovascular disease and all-cause mortality: Guangzhou Biobank Cohort Study and meta-analyses. Eur J Nutr. 2019; 58(2):785-96.A study evaluating American population cohorts, considering an average consumption of 0.5 eggs per day (3 to 4 eggs per week), concluded that each additional 0.5 eggs consumed per day is associated with a 6% increase in risk of CVD (95% CI: 1.03-1.10) and an 8% increase in all-cause mortality (95% CI: 1.04-1.11). However, after statistical adjustment for cholesterol consumption, both associations were no longer significant, with an adjusted hazard ratio of 0.99 (95% CI: 0.93-1.05) for CVD incidence and an adjusted hazard ratio of 1.03 (95% CI: 0.97-1.09) for all-cause mortality.447447. Zhong VW, Van Horn L, Cornelis MC et al. Associations of dietary cholesterol or egg consumption with incident cardiovascular disease and mortality. JAMA. 2019; 321(11):1081-95.A recent analysis of the results of 3 prospective cohort studies that included 177 000 individuals showed that moderate egg consumption (1 egg/day) was not associated with an increased risk of mortality or CVD.455455. Dehghan M, Mente A, Rangarajan S, et al. Association of egg intake with blood lipids, cardiovascular disease, and mortality in 177,000 people in 50 countries. Am J Clin Nutr . 2020;111(4):795-803.

In high cardiovascular risk individuals, the degree of atherosclerosis (assessed by coronary angiography) was lower among those who consumed > 1 egg per week compared to those who consumed < 1 egg per week.456456. Chagas P, Caramori P, Galdino TP et al. Egg consumption and coronary atherosclerotic burden. Atherosclerosis. 2013;229(2):381-4.Similarly, the consumption of 2 eggs per day for 6 weeks did not affect endothelial function in individuals with CAD.457457. Katz DL, Gnanaraj J, Treu JA et al. Effects of egg ingestion on endothelial function in adults with coronary artery disease: A randomized, controlled, crossover trial. Am Heart J. 2015; 169(1):162-9.

A systematic review of cohort studies evaluating patients with T2D concluded that the consumption of at least 1 egg per day increased the risk of developing CVD by 69% (AMI, CAD, stroke, and ischemic heart disease) when compared to the consumption of < 1 egg per week, with no association with increased mortality.439439. Shin JY, Xun P, Nakamura Y et al. Egg consumption in relation to risk of cardiovascular disease and diabetes: a systematic review and meta-analysis. Am J Clin Nutr. 2013; 98(1):146-59.

With regard to HF, a Swiss study assessing the results of two prospective cohorts concluded that daily consumption of 1 egg did not increase the risk of HF among men and women, but the consumption of > 1 egg per day increased the risk of HF by 30% in men, and the causal effect remains unclear.444444. Larsson SC, Åkesson A, Wolk A. Egg consumption and risk of heart failure, myocardial infarction, and stroke: results from 2 prospective cohorts. Am J Clin Nutr. 2015; 102(5):1007-13.

A review of current evidence is not able to establish a causal relationship between egg consumption and CVD. However, divergent results of observational studies suggest caution in egg consumption, especially among patients with T2D and those who are hyper-responsive to dietary cholesterol. Because eggs have high nutrient and protein density, they may be included in the diet as long as being part of a healthy dietary pattern.

14.1. Trimethylamine N-oxide in Cardiovascular Diseases

Studies have shown that the gut microbiota is involved in the development of CAD,458458. Wu ZX, Li SF, Chen H et al. The changes of gut microbiota after acute myocardial infarction in rats. PLoS One. 2017; 12(7):e0180717.and trimethylamine N-oxide (TMAO) is an emerging research focus on the study of atherosclerosis progression. TMAO is an amine oxide that can be naturally found in the diet but also be metabolized from choline (abundant in eggs), carnitine (red meat), betaine, and phosphatidylcholine. These precursors are converted to trimethylamine (TMA) in the small intestine by specific bacteria such as Firmicutes, proteobacteria, and actinobacteria found in the gut microbiota.459459. Davies A, Lüscher TF. The red and the white, and the difference it makes. Eur Heart J. 2019; 40(7):595-7. , 460460. Lemos BS, Medina-Vera I, Malysheva OV et al. Effects of Egg Consumption and Choline Supplementation on Plasma Choline and Trimethylamine-N-Oxide in a Young Population. J Am Coll Nutr. 2018 May;1-8. TMA is absorbed and oxidized to TMAO through a reversible reaction in the liver, then catalyzed by the enzyme flavin-containing monooxygenase 3.461461. Jonsson AL, Bäckhed F. Role of gut microbiota in atherosclerosis. Nat Rev Cardiol. 2017;14(2):79-87.

Fish seems to be the largest food source of TMAO. Studies assessing fish intake show an increase in plasma TMAO concentrations (50 times higher) when compared to other food sources of carnitine or choline. Nevertheless, urinary excretion of TMAO and dimethylamine (derived from TMA) following fish consumption is higher compared to that of meat, dairy, fruits, vegetables, or grains.462462. Canyelles M, Tondo M, Cedó L et al. Trimethylamine N-oxide: A link among diet, gut microbiota, gene regulation of liver and intestine cholesterol homeostasis and HDL function. Int J Mol Sci. 2018; 19(10). pii: E3228.

463. Ding L, Chang M, Guo Y et al. Trimethylamine-N-oxide (TMAO)-induced atherosclerosis is associated with bile acid metabolism. Lipids Health Dis. 2018; 17(1):286.
- 464464. Cho CE, Caudill MA. Trimethylamine-N-Oxide: Friend, Foe, or Simply Caught in the Cross-Fire? Trends Endocrinol Metab. 2017; 28(2):121-130.

Elevated plasma TMAO concentrations correlated with increased risk of major cardiovascular events, prevalence of CVD, poorer prognosis, and increased risk of death.461461. Jonsson AL, Bäckhed F. Role of gut microbiota in atherosclerosis. Nat Rev Cardiol. 2017;14(2):79-87.This is because TMAO can exacerbate the inflammatory response in the vascular wall and induce the production of ROS. More recently, the role of TMAO in modulating cholesterol and bile acid metabolism and promoting atherosclerosis progression has been demonstrated.463463. Ding L, Chang M, Guo Y et al. Trimethylamine-N-oxide (TMAO)-induced atherosclerosis is associated with bile acid metabolism. Lipids Health Dis. 2018; 17(1):286.

A mechanism by which TMAO may contribute to the progression of CVD is through an increased expression of scavenger receptors, which are responsible for the uptake of oxidized LDL, including class A scavenger receptors and surface protein CD36 in macrophages, both involved in cholesterol absorption. Some studies also suggest that TMAO prevents reverse cholesterol transport, which may contribute to the pathogenesis of CVD, promoting cholesterol accumulation in macrophages.464464. Cho CE, Caudill MA. Trimethylamine-N-Oxide: Friend, Foe, or Simply Caught in the Cross-Fire? Trends Endocrinol Metab. 2017; 28(2):121-130.

Vascular events such as AMI and stroke in individuals with high plasma TMAO concentrations may be related to increased platelet activity due to cytoplasmic release of calcium, which may predispose the person to hypercoagulation and increased thrombotic events.465465. QI J, You T, Li J et al. Circulating trimethylamine N-oxide and the risk of cardiovascular diseases: a systematic review and meta-analysis of 11 prospective cohort studies. J Cell Mol Med. 2018; 22(1):185-94. , 466466. Wang Z, Bergeron N, Levison BS et al. Impact of chronic dietary red meat, white meat, or non-meat protein on trimethylamine N-oxide metabolism and renal excretion in healthy men and women. Eur Heart J. 2019; 40(7):583-94.

A meta-analysis of studies recruiting over 26 000 participants followed up for about 4 years showed an increased relative risk (7.6%) of all-cause mortality for each increment of TMAO.467467. Schiattarella GG, Sannino A, Toscano E et al. Gut microbe-generated metabolite trimethylamine-N-oxide as cardiovascular risk biomarker: A systematic review and dose-response meta-analysis. Eur Heart J. 2017; 38(39):2948-56.

A recent study evaluated the relationship of consumption of different protein sources (red meat, white meat, or vegetable protein) in TMAO metabolism. Long-term red meat consumption increased plasma TMAO concentrations by more than 3 times, as well as urinary excretion, compared to the other groups.468468. Missimer A, Fernandez ML, DiMarco DM et al. Compared to an oatmeal breakfast, two eggs/day increased plasma carotenoids and choline without increasing trimethyl amine N-Oxide concentrations. J Am Coll Nutr. 2018; 37(2):140-8.Studies on egg consumption have not found an association between egg consumption and increased TMAO. A study of 50 healthy participants showed that the consumption of 2 eggs (400 mg choline) per day did not change plasma TMAO concentrations.460460. Lemos BS, Medina-Vera I, Malysheva OV et al. Effects of Egg Consumption and Choline Supplementation on Plasma Choline and Trimethylamine-N-Oxide in a Young Population. J Am Coll Nutr. 2018 May;1-8. , 468468. Missimer A, Fernandez ML, DiMarco DM et al. Compared to an oatmeal breakfast, two eggs/day increased plasma carotenoids and choline without increasing trimethyl amine N-Oxide concentrations. J Am Coll Nutr. 2018; 37(2):140-8.

14.2. Hepatic Steatosis

Animal experiments suggest that high-cholesterol diets induce the progression of NASH, especially if combined with high-fat and high-energy diets.469469. Wang X, Tanaka N, Hu X et al. A high-cholesterol diet promotes steatohepatitis and livertumorigenesis in HCV core gene transgenic mice. Arch Toxicol. 2019; 93(6):1727-8.

470. Ioannou GN. The Role of Cholesterol in the Pathogenesis of NASH. TrendsEndocrinolMetab. 2016; 27(2):84-95.

471. Subramanian S, Goodspeed L, Wang S et al. Dietary cholesterol exacerbateshepatic steatosis and inflammation in obese LDL receptor-deficient mice. J Lipid Res. 2011; 52(9):1626-35.
- 472472. Savard C, Tartaglione EV, Kuver R et al. Synergistic interaction of dietary cholesteroland dietary fat in inducing experimental steatohepatitis. Hepatology. 2013; 57(1):81-92. However, there are no human studies showing the effect of dietary cholesterol on the development of hepatic steatosis. The current guideline for the treatment of NAFLD makes no reference to cholesterol consumption and etiology or treatment of this disease.297297. Chalasani N, Younossi Z, Lavine JE et al. The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases. Hepatology. 2018; 67(1):328-57.

15. Interesterified Fats

Interesterified fats have been used as a substitute for trans fatty acids, which are prepared using partial hydrogenation of vegetable oils. Interesterified fats are prepared using a fully hydrogenated solid base that is blended with a vegetable oil. Blended solid fractions such as palm stearin or lauric acid (found in coconut oil) and palm olein are used to prepare this solid base.2626. Tarrago-Trani MT, Phillips KM, Lemar LE et al. New and existing oils and fats used in products with reduced trans-fatty acids content. J Am Diet Assoc. 2006; 106(6):867-80.

The main characteristic of interesterified fats is the lack of trans fatty acids; however, they have a high concentration of SFAs. Interesterification is carried out through a chemical process that uses sodium methoxide as a catalyst, which promotes rearrangement of fatty acids in the glycerol molecule.2626. Tarrago-Trani MT, Phillips KM, Lemar LE et al. New and existing oils and fats used in products with reduced trans-fatty acids content. J Am Diet Assoc. 2006; 106(6):867-80.This forms TGs with new physical, organoleptic, and chemical properties, with enriched SFAs in the sn-2 position of glycerol, which is normally occupied by PUFAs in vegetable oils.473473. Berry S. Triacylglycerol structure and interesterification of palmitic and stearic acid-rich fats: an overview and implications for cardiovascular disease. Nutr Res Rev. 2009; 22(1):3-17.In this process, a large amount of TGs consisting of 3 SFAs are formed. Palmitic acid (more frequently) and stearic acid are the fatty acids most used in the food industry to replace trans fat.473473. Berry S. Triacylglycerol structure and interesterification of palmitic and stearic acid-rich fats: an overview and implications for cardiovascular disease. Nutr Res Rev. 2009; 22(1):3-17.

15.1. Studies in Animals

The consumption of a normolipidic diet containing interesterified fat produced from soybean oil, compared to a diet with soybean oil, by Wistar rats for 8 weeks resulted in higher expression of ATF3, an ER stress marker, and a higher concentration of the inflammatory cytokine TNF-α, with no difference in weight gain and glucose tolerance. However, greater weight gain was observed after 16 weeks of treatment, together with increased retroperitoneal adipose tissue mass and impaired glucose tolerance in the group that consumed interesterified fat.474474. Miyamoto JÉ, Ferraz ACG, Portovedo M et al. Interesterified soybean oil promotes weight gain, impaired glucose tolerance and increased liver cellular stress markers. J Nutr Biochem. 2018 Sep; 59:153-9.

The effect of coconut oil, rice bran oil or sesame oil blended or subjected to enzymatic interesterification, with SFA/MUFA/PUFA ratio of 1:1:1 and PUFA/SFA ratio of 0.8:1, consumed for 60 days, was also evaluated in Wistar rats.475475. Reena MB, Lokesh BR. Hypolipidemic effect of oils with balanced amounts of fatty acids obtained by blending and interesterification of coconut oil with rice bran oil or sesame oil. J Agric Food Chem. 2007; 55(25):10461-9In animals fed interesterified oils, concentrations of TC, LDLc, and TG were reduced compared to animals fed blended oils. This was due to an increased expression of hepatic LDL receptor and the protein SREBP2, which induces cholesterol synthesis, compared to the same fat that had not undergone interesterification.476476. Reena MB, Gowda LR, Lokesh BR. Enhanced hypocholesterolemic effects of interesterified oils are mediated by upregulating LDL receptor and cholesterol 7-α- hydroxylase gene expression in rats. J Nutr. 2011; 141(1):24-30.

Long-term consumption of a high-fat diet enriched with interesterified fat containing palmitic acid by LDL receptor knockout mice did not increase plasma cholesterol concentrations. However, there an increased concentration of cholesterol in LDL particles, a condition that resulted in higher atherosclerotic lesion, together with greater arterial macrophage infiltration.477477. Afonso MS, Lavrador MS, Koike MK et al. Dietary interesterified fat enriched with palmitic acid induces atherosclerosis by impairing macrophage cholesterol efflux and eliciting inflammation. J Nutr Biochem. 2016 Jun; 32:91-100.Another study by the same research group demonstrated that long-term consumption of those diets in the same animal model led to greater weight gain, expanded adipose tissue, and adipocyte hypertrophy with greater inflammation, evidenced by increased pIKK and TNF-α levels.478478. Lavrador MSF, Afonso MS, Cintra DE et al. Interesterified fats induce deleterious effects on adipose tissue and liver in LDLr-KO mice. Nutrients. 2019; 11(2). pii: E466.

Other studies have evaluated the effect of a normolipidic diet containing interesterified fat rich in palmitic acid by female animals during pregnancy and lactation on the offspring. The results show that interesterified fat consumption predisposes the offspring to the development of obesity in adulthood,479479. Magri TP, Fernandes FS, Souza AS et al. Interesterified fat or palm oil as substitutes for partially hydrogenated fat in maternal diet can predispose obesity in adult male offspring. Clin Nutr. 2015; 34(5):904-10. , 480480. Misan V, Estato V, de Velasco PC et al. Interesterified fat or palm oil as substitutes for partially hydrogenated fat during the perinatal period produces changes in the brain fatty acids profile and increases leukocyte- endothelial interactions in the cerebral microcirculation from the male offspring in adult life. Brain Res. 2015 Aug; 1616:123-33. suggesting a negative epigenetic influence. In addition, a study conducted by Misan et al. (2015)480480. Misan V, Estato V, de Velasco PC et al. Interesterified fat or palm oil as substitutes for partially hydrogenated fat during the perinatal period produces changes in the brain fatty acids profile and increases leukocyte- endothelial interactions in the cerebral microcirculation from the male offspring in adult life. Brain Res. 2015 Aug; 1616:123-33.found that, after 90 days of life, the offspring showed greater weight gain as well as lower EPA concentration and greater leukocyte circulation in the brain, with no increase in TLR4.

15.2. Studies in Humans

In humans, both partially hydrogenated and interesterified soybean oil provided an increase in the LDLc/HDLc ratio when compared to palm oil. In addition to the change in plasma lipid concentrations, interesterified fat had an adverse effect on glucose metabolism, reducing plasma insulin concentration and increasing fasting glucose.481481. Sundram K, Karupaiah T, Hayes KC. Stearic acid-rich interesterified fat and trans-rich fat raise the LDL/HDL ratio and plasma glucose relative to palm olein in humans. Nutr Metab. (London) 2007 Jan; 4:3.However, a more recent study showed no changes in fasting glucose and insulin following interesterified fat consumption.482482. Filippou A, Teng KT, Berry SE et al. Palmitic acid in the sn-2 position of dietary triacylglycerols does not affect insulin secretion or glucose homeostasis in healthy men and women. Eur J Clin Nutr. 2014; 68(9):1036-41.However, when compared to margarine containing high levels of linoleic acid and moderate levels of trans fat, the consumption of margarines containing palm oil (lauric, myristic, palmitic, oleic, and linoleic acids) or interesterified palm oil favored an increase in LDLc concentrations in hypercholesterolemic men.483483. Nestel PJ, Noakes M, Belling GB et al. Effect on plasma lipids of interesterifying a mix edible oils. Am J Clin Nutr. 1995; 62(5):950-5.A likely explanation to those different results is that Sundram et al.481481. Sundram K, Karupaiah T, Hayes KC. Stearic acid-rich interesterified fat and trans-rich fat raise the LDL/HDL ratio and plasma glucose relative to palm olein in humans. Nutr Metab. (London) 2007 Jan; 4:3.used interesterified fat composed of stearic acid, while Filippou et al.482482. Filippou A, Teng KT, Berry SE et al. Palmitic acid in the sn-2 position of dietary triacylglycerols does not affect insulin secretion or glucose homeostasis in healthy men and women. Eur J Clin Nutr. 2014; 68(9):1036-41.used palmitic acid. Both studies compared interesterified fat with palm oil.

Additionally, interesterification has been shown to transfer significant amounts of palmitic acid to the sn-2 position and UFAs to the sn-1 and sn-3 positions, which had an effect on plasma chylomicrons.484484. Wang CH, Kuksis A, Manganaro F. Studies of the substrate specificity of purified human milk lipoprotein lipase. Lipids. 1982; 17(4):278-84.

Studies also showed that interesterified fat induced a lower postprandial plasma TG concentration in healthy menopausal women,485485. Yli-Jokipii K, Kallio H, Schwab U et al. Effects of palm oil and transesterified palm oil on chylomicron and VLDL triacylglycerol structures and postprandial lipid response. J Lipid Res. 2001; 42(10):1618-25.in healthy young adults,486486. Sanders TA, Filippou A, Berry SE et al. Palmitic acid in the sn-2 position of triacylglycerols acutely influences postprandial lipid metabolism. Am J Clin Nutr. 2011;94(6):1433-41.and in hypertriglyceridemic adults487487. Hall WL, Brito MF, Huang J et al. An interesterified palm olein test meal decreases early-phase postprandial lipemia compared to palm olein: a randomized controlled trial. Lipids. 2014; 49(9):895-904.compared to palm oil.

Regarding the influence of nutritional status and the intake of interesterified fat consumption on lipoprotein profile,488488. Robinson DM, Martin NC, Robinson LE et al. Influence of interesterification of a stearic Acid-rich spreadable fat on acute metabolic risk factor. Lipids. 2009;44(1):17-26.interesterification was found to increase postprandial TG concentration (85%) in obese individuals. This was not observed in healthy individuals, suggesting that interesterification may affect them differently from those who are at risk of developing CVD and T2D.

In healthy individuals, interesterification did not change plasma lipid concentrations but favored a lower concentration of D-dimer, a fibrin degradation product associated with risk of CVD.489489. Meijer GW, Weststrate JA. Interesterification of fats in margarine: effect on blood lipids, blood enzymes, and hemostasis parameters. Eur J Clin Nutr. 1997; 51(8):527-34.

To date, there is no scientific evidence for reaching a conclusion on the effect of the interesterification process on metabolic parameters, development of atherosclerosis, and cardiovascular outcome. However, it is important to note the high content of SFAs in interesterified fat that is currently used by the food industry.

16. Medium-chain Triglycerides

Medium-chain TGs are defined as structured lipids composed of a mixture of saturated-chain fatty acids, containing from 6 to 12 carbons, formed by caproic acid (C6: 1 to 2%), caprylic acid (C8: 65 to 75%), capric acid (C10: 25 to 35%), and lauric acid (C12: 1 to 2%).367367. Bach A, Babayan V. Medium-chain triglycerides: an update. Am J Clin Nutr. 1982; 36(5):950-62. , 490490. Bach AC, Ingenbleek Y, Frey A. The usefulness of dietary medium-chain triglycerides in body weight control: fact or fancy? J Lipid Res. 1996; 37(4):708-26. The fatty acids of medium-chain TGs are obtained by fractionation of coconut or palm oils.491491. Williams L, Wilson DP. Editorial commentary: Dietary management of familial chylomicronemia syndrome. J Clin Lipidol. 2016; 10(3):462-5.Except for lauric acid, the other fatty acids are absorbed via the portal system and, because they are not incorporated into chylomicrons, they do not induce an increase in plasma TG levels.491491. Williams L, Wilson DP. Editorial commentary: Dietary management of familial chylomicronemia syndrome. J Clin Lipidol. 2016; 10(3):462-5. , 492492. Hill JO, Peters JC, Swift LL et al. Changes in blood lipids during six days of overfeeding with medium or long chain triglycerides. J Lipid Res. 1990; 31(3):407-16. Lauric acid is preferably transported via the lymphatic system by chylomicrons.3838. McDonald GB, Saunders DR, Weidman M et al. Portal venous transport of long-chain fatty acids absorbed from rat intestine. Am J Physiol. 1980; 239(3):G141-50. , 493493. Swift LL, Hill JO, Peters JC et al. Medium-chain fatty acids: evidence for incorporation into chylomicron triglycerides in humans. Am J Clin Nutr. 1990;52(5):834-6. For this reason, for the management of familial hyperchylomicronemia, when LPL is absent, the use of medium-chain TGs composed mostly of caproic, caprylic, and capric acids is indicated.491491. Williams L, Wilson DP. Editorial commentary: Dietary management of familial chylomicronemia syndrome. J Clin Lipidol. 2016; 10(3):462-5.

17. Familial Chylomicronemia Syndrome

Familial chylomicronemia syndrome (FCS) is a rare autosomal recessive disease that affects 1 to 2 people per million.494494. Burnett JR, Hooper AJ, Hegele RA. Familial lipoprotein lipase deficiency. In: Adam MP, Ardinger HH, Pagon RA et al., editors. GeneReviews. Seattle (WA): University of Washington, Seattle. p. 1993–2018, Available at: https://www.ncbi.nlm.nih.gov/books/ NBK1308/. Accessed June 09, 2020.
https://www.ncbi.nlm.nih.gov/books/ NBK1...
, 495495. Pouwels ED, Blom DJ, Firth JC et al. Severe hypertriglyceridaemia as a result of familial chylomicronaemia: the Cape Town experience. S Afr Med J. 2008;98:105–108. It is characterized by severe hypertriglyceridemia, even when fasting, due to a deficiency in the enzyme LPL or in other proteins required for normal lipase activity. The most common homozygous mutations in FCS are found in the genes LPL, APOA5, GPBIHBP1 (glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1), APOC2, and LMF1 (lipase maturation factor 1), but compound heterozgous mutations may also appear in different genes that cause FCS.496496. Brahm AJ, Hegele RA. Chylomicronaemia- current diagnosis and future therapies. Nat Rev Endocrinol. 2015;11:352–362.

497. Moulin P, Dufour R, Averna M et al. Identification and Diagnosis of Patients With Familial Chylomicronaemia Syndrome (FCS): Expert Panel Recommendations and Proposal of an “FCS Score”. Atherosclerosis 2018;275:265-272.
- 498498. Witzum JL, Gaudet D, Freedman SD et al. Volanesorsen and Triglyceride Levels in Familial Chylomicronemia Syndrome. N Engl J Med 2019; 381:531-542. TG concentrations are often 10 to 100 times higher than those found in normal individuals (< 150 mg/dL), ranging from 1500 to 15 000 mg/dL or higher.499499. Stroes E, Moulin P, Parhofer KG et al. Diagnostic algorithm for familial chylomicronemia syndrome. Atheroscler Suppl. 2017;23:1–7. , 500500. Hegele RA, Ginsberg HM, Chapman MJ et al, European Atherosclerosis Society Consensus Panel. The polygenic nature of hypertriglyceridaemia: implications for definition, diagnosis and management. Lancet Diabetes Endocrinol. 2014;2:655–666. Hypertriglyceridemia in FCS stems from the inability to metabolize TGs and other fats. TGs are normally metabolized via an LPL-dependent pathway.500500. Hegele RA, Ginsberg HM, Chapman MJ et al, European Atherosclerosis Society Consensus Panel. The polygenic nature of hypertriglyceridaemia: implications for definition, diagnosis and management. Lancet Diabetes Endocrinol. 2014;2:655–666.Although an LPL-independent pathway exists, it is not sufficient to compensate for the loss of LPL function. In FCS, accumulation of chylomicrons and their remnants cannot be metabolized, and they build up in the plasma. In the pancreas, there is impairment of blood flow and activation of the inflammatory process, resulting in pancreatitis,501501. Gan SI, Edwards AL, Symonds CJ, Beck PL. Hypertriglyceridemia - induced pancreatitis: A case-based review. World J Gastroenterol. 2006;12:7197–7202.

502. Valdivielso P, Ramirez-Bueno A, Ewald N. Current knowledge of hypertriglyceridemic pancreatitis. Eur J Intern Med. 2014;25:689–694.
- 503503. Brown WV, Goldberg IJ, Young SG. JCL Roundtable: Hypertriglyceridemia due to defects in lipoprotein lipase function. J Clin Lipidol. 2015;9:274–280. and this condition accounts for 10% of all causes of pancreatitis501501. Gan SI, Edwards AL, Symonds CJ, Beck PL. Hypertriglyceridemia - induced pancreatitis: A case-based review. World J Gastroenterol. 2006;12:7197–7202.. Patients with elevated TG-induced pancreatitis have more severe conditions, longer hospitalizations, required stay in the intensive care unit, high rates of progression to pancreatic necrosis, and a higher frequency of organ failure and mortality.504504. Nawaz H, Koutroumpakis E, Easler J et al. Elevated serum triglycerides are independently associated with persistent organ failure in acute pancreatitis. Am J Gastroenterol. 2015;110:1497–1503.Pancreatitis may also progress to a chronic condition, with exocrine and endocrine pancreatic insufficiency, including pancreatic diabetes (type 3c), which can be fatal. Recurrent abdominal pain, lipemia retinalis, hepatosplenomegaly, lipemic plasma, eruptive xanthoma, and poor quality of life are other common findings.505505. Yang F, Wang Y, Sternfeld L et al. The role of free fatty acids, pancreatic lipase and Ca21 signalling in injury of isolated acinar cells and pancreatitis model in lipoprotein lipase-deficient mice. Acta Physiol (Oxf). 2009;195:13–28.

506. Berglund L, Brunzell JD, Goldberg AC et al. Endocrine society. Evaluation and treatment of hypertriglyceridemia: An Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2012;97:2969–2989.

507. Gaudet D, Methot T, Dery S et al. Efficacy and long-term safety of alipogene tiparvovec (AAV1-LPLS447X) gene therapy for lipoprotein lipase deficiency: An open-label trial. Gene Ther. 2013;20:361–369.

508. Davidson M, Stevenson M, Hsieh A et al. The burden of familial chylomicronemia syndrome: interim results from the IN-FOCUS study. Expert Rev Cardiovasc Ther. 2017;15:415–423.

509. Brunzell JD, Deeb SS. Familial lipoprotein lipase deficiency, apo C-II deficiency and hepatic lipase deficiency. In: Scriver CR, Beaudet AL, Sly WS, Valle D, editors. The Metabolic and Molecular Bases of In- herited Disease. 8th ed. New York, NY: McGraw-Hill, 2001. p. 2789–2816.
- 510510. Ahmad Z, Halter R, Stevenson M. Building a better understanding of the burden of disease in familial chylomicronemia syndrome. Expert Rev Clin Pharmacol. 2017;10:1–3. Because those patients are not able to metabolize TGs, the current nutritional guidance consists of a very-low-fat diet (< 10-15% of total energy, or about 15-20 g of fat per day), restriction of refined carbohydrates, and alcohol withdrawal.511511. Williams L, Rhodes KS, Karmally W et al, for the patients and families living with FCS. Familial chylomicronemia syndrome: Bringing to life dietary recommendations throughout the life span. J Clin Lipidol. 2018;12:908-919.Additionally, individuals with FCS of all ages should be regularly monitored for the consumption of micronutrients, particularly fat-soluble vitamins.511511. Williams L, Rhodes KS, Karmally W et al, for the patients and families living with FCS. Familial chylomicronemia syndrome: Bringing to life dietary recommendations throughout the life span. J Clin Lipidol. 2018;12:908-919.Depending on individual tolerability, medium-chain TGs may be indicated for energy intake in the diet.491491. Williams L, Wilson DP. Editorial commentary: Dietary management of familial chylomicronemia syndrome. J Clin Lipidol. 2016; 10(3):462-5.Medications that are known to elevate TGs should also be used with caution, such as diuretics, beta-blockers, systemic corticosteroids, retinoids, bile acid sequestrants, protease inhibitors, and antidepressants (sertraline). Supplementation with ω3 fatty acids and other drugs used to treat hypertriglyceridemia has been inconsistent in reducing TGs.512512. Yuan G, Al-Shali KZ, Hegele RA. Hypertriglyceridemia: its etiology, effects and treatment. CMAJ. 2007;176:1113–1120.

513. Connor WE, DeFrancesco CA, Connor SL. N-3 fatty acids from fish oil. Effects on plasma lipoproteins and hypertriglyceridemic patients. Ann NY Acad Sci. 1993;683:16–34.
- 514514. Pschierer V, Richter WO, Schwandt P. Primary chylomicronemia in patients with severe familial hypertriglyceridemia responds to long- term treatment with (n-3) fatty acids. J Nutr. 1995;125:1490–1494.

18. Practical Aspects of Nutritional Intervention

The nutritional composition of the diet must be adjusted to the objectives proposed for each individual, considering the individual’s energy needs and cultural preferences. Several nutritional strategies can contribute to cardiovascular prevention provided they are based on the exclusion of trans fats, adequate SFA intake, and proportionally greater UFA intake, in addition to encouraging the consumption of fruits, vegetables, and whole grains.99. Grundy SM, Stone NJ, Bailey AL et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2019; 139(25):e1082-143 , 515515. Arnett DK, Blumenthal RS, Albert MA et al. 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2019; 140(11):e596-e646

Foods of animal origin – such as meat, milk, and dairy products – naturally have a higher SFA content, while vegetable oils have a higher UFA content, except for coconut and palm oils, which are rich in SFAs. Among vegetable oils ( Table 1 ), soybean, canola and corn oils are most used, which have a good distribution of fatty acids. Soybean and canola oils have an additional advantage over corn oil: they have lower SFA content and higher ALA (ω3) content, which is essential for humans and is a precursor to EPA and DHA, also found in fish (Figures 1 and 2 ).

The amount of fat from meat varies according to the type of cut. Therefore, lean meat cuts, such as pork loin and pork tenderloin, have a SFA content similar to that of commonly recommended beef cuts, such as knuckle and rump steak ( Figure 3 ), making it possible to expand the options of protein-source foods with a cardioprotective focus.

Whole-milk dairy products have higher amounts of SFA than those produced with skimmed or semi-skimmed milk. Regarding cheese, those with lower water content and harder, such as parmesan cheese, proportionally have a higher SFA concentration than Brazilian cream cheese, Minas cheese, and ricotta cheese ( Figure 4 ). The choice between product types should consider the serving size, since even dairy products with less fat content may be important sources of SFAs if consumed in large amounts.

Nutritional guidance should enable consumers to understand the composition of foods, especially processed foods, since the amount and type of nutrients, especially fats, may vary within the same product type depending on the manufacturer (Table S1, Supplementary Material). In this context, adequate food labeling becomes essential for the processes of nutritional education and consumer choice. Another important aspect to be considered is food preparation. Deep frying, for example, can add a large amount of fat to food items, thus considerably increasing the energy intake. It is important to note that vegetable oils, which are sources of ω3 and ω6, should not be substituted for tropical oils (palm and coconut oils) or animal fats (lard and butter), as they are rich in SFAs and do not provide adequate amounts of essential dietary fatty acids. This guidance is in line with the latest AHA recommendation for cardiovascular risk prevention88. Eckel RH, Jakicic JM, Ard JD et al; American College of Cardiology/American Heart Association Task Force on Practice Guidelines. 2013 AHA/ACC guideline on lifestyle management to reduce cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014; 129(25 Suppl 2):S76-99. , 99. Grundy SM, Stone NJ, Bailey AL et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2019; 139(25):e1082-143 and with the ESC/EAS guidelines, which recommend occasional use of tropical oils in small amounts.1010. Mach F, Baigent C, Catapano AL et al; ESC Scientific Document Group. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J. 2020; 41(1):111-88.

Finally, care should be taken in recommending the use of dietary supplements that have not been scientifically proven to provide health benefits. Therefore, non-pharmacological strategies to reduce cardiovascular risk should consider the available evidence that points to benefits, safety, costs, and tolerability, in addition to possible effects of drug-nutrient interactions. Another important aspect is that the misuse of supplements may compromise adherence to both pharmacological and nutritional treatment.516516. Lloyd-Jones DM, Morris PB, Ballantyne CM et al. 2017 Focused Update of the 2016 ACC Expert Consensus Decision Pathway on the Role of Non-Statin Therapies for LDL-Cholesterol Lowering in the Management of Atherosclerotic Cardiovascular Disease Risk: A Report of the American College of Cardiology Task Force on Expert Consensus Decision Pathways. J Am Coll Cardiol. 2017; 70(14):1785-822.

19. Labeling and Trans Fatty Acids

The use of trans fats brings a number of advantages to the food industry, such as cost reduction, longer shelf life, high melting point, and wide possibilities of use. However, their association with increased cardiovascular risk is clearly established, so that several international and national guidelines recommend their exclusion from the diet. Reducing NCDs is one of the goals of the WHO Global Strategy on Diet, Physical Activity and Health,517517. Nishida C, Uauy R. WHO Scientific Update on health consequences of trans fatty acids: introduction. Eur J Clin Nutr. 2009; 63(Suppl 2):S1-4.which, in line with international guidelines,99. Grundy SM, Stone NJ, Bailey AL et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2019; 139(25):e1082-143 , 1010. Mach F, Baigent C, Catapano AL et al; ESC Scientific Document Group. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J. 2020; 41(1):111-88. , 518518. Sacks FM, Lichtenstein AH, Wu JHY et al. Dietary Fats and Cardiovascular Disease: A Presidential Advisory From the American Heart Association. Circulation. 2017; 136(3):e1-23. recommends eliminating trans fats from the diet.517517. Nishida C, Uauy R. WHO Scientific Update on health consequences of trans fatty acids: introduction. Eur J Clin Nutr. 2009; 63(Suppl 2):S1-4.

In Brazil, the National Health Surveillance Agency (ANVISA), which is responsible for food labeling regulation, established in 2003 that food labels must state the amount per serving of trans fats present in the product.519519. Agência Nacional de Vigilância Sanitária (Anvisa). RDC Nº 360, de 23 de dezembro de 2003. Regulamento técnico sobre rotulagem nutricional de alimentos embalados. Disponível em: http://portal.anvisa.gov.br/documents/33880/2568070/res0360_23_12_2003.pdf/5d4fc713-9c66-4512-b3c1-afee57e7d9bc. Acesso em 11 de janeiro de 2019.
http://portal.anvisa.gov.br/documents/33...
However, despite the mandatory requirement, ANVISA resolution allows foods that contain an amount less than or equal to 0.2 g per serving to be declared as trans fat-free (labeled as “zero trans fat” or “does not contain trans fats”). It is important to note that this tolerance may lead to increased trans fat intake through the high intake of foods declared as trans fat-free, but which contain values close to 0.2 g per serving.520520. Pinto ALD, Miranda TLS, Ferraz VP et al. Determinação e verificação de como a gordura trans é notificada nos rótulos de alimentos, em especial naqueles expressos “0% gordura trans”. Braz. J. Food Technol. 2016 May;19:e2015043.In addition, the serving declared on the label and considered trans fat-free is often smaller than the average amount of the product consumed.520520. Pinto ALD, Miranda TLS, Ferraz VP et al. Determinação e verificação de como a gordura trans é notificada nos rótulos de alimentos, em especial naqueles expressos “0% gordura trans”. Braz. J. Food Technol. 2016 May;19:e2015043.Therefore, it is important that consumers receive guidance on how to identify the presence \of trans fats in the list of ingredients in order to avoid the intake of foods containing trans fats.

20. Final Considerations

This position statement shows that recent findings regarding the effects of fatty acids on intracellular signaling pathways and the results of clinical and epidemiological studies support the current nutritional guidelines for the prevention and treatment of cardiometabolic diseases. The grade of recommendation and level of evidence in regard of the effect of fatty acids on cardiovascular diseases are shown in table 2 and 3. International guidelines recommend eliminating trans fatty acids from the diet, reducing SFA intake, and including, in appropriate amounts, foods that are sources of UFAs. Epidemiological studies show that both excessive SFA intake and insufficient PUFA intake are associated with increased cardiovascular risk. In addition, the effects of fatty acid intake still depend on the dietary pattern in which they are consumed, since the replacement of SFAs with refined carbohydrates can increase cardiovascular risk. However, when isocalorically replaced with UFAs or even with complex carbohydrates, cardiovascular outcomes tend to be favorable. The benefits attributed to an adequate fatty acid profile are only observed in the presence of healthy eating patterns.

Table 2
– Dietary Fatty Acids and Cardiovascular Risk

21. Nutritional Amounts of Fatty Acids and Cholesterol in Foods

Table 1
– Nutritional table with amounts of fatty acids and cholesterol in oils and fats. Food composition per 100 g of edible portion: fatty acids and cholesterol

Figure 1
– Content of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in fish (g/100 g)

Figure 2
– Content of monounsaturated fatty acids (MUFAs), polyunsaturated fatty acids (PUFAs), and saturated fatty acids (SFAs) in vegetable oils (g/100 g)

Figure 3
– Content of monounsaturated fatty acids (MUFAs), polyunsaturated fatty acids (PUFAs), saturated fatty acids (SFAs), and trans fatty acids in meats and eggs (g/100 g)

Figure 4
– Total content of saturated fatty acids in dairy products (g/100 g)

22. Grade of Recommendations and Level of Evidence: Fatty Acids and Cardiovascular Disease

Table 3
– Supplementation of omega-3 and cardiovascular risk

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  • How to cite this Statement: Izar MCO, Lottenberg AM, Giraldez VZR, Santos Filho RDS, Machado RM, Bertolami A, et al. Position Statement on Fat Consumption and Cardiovascular Health – 2021. Arq Bras Cardiol. 2021; 116(1):160-212
    Note: These statements are for information purposes and should not replace the clinical judgment of a physician, who must ultimately determine the appropriate treatment for each patient.
    Development: Atherosclerosis Department (Departamento de Aterosclerose – DA) of the Brazilian Society of Cardiology (Sociedade Brasileira de Cardiologia – SBC)
    Norms and Guidelines Council: Brivaldo Markman Filho, Antonio Carlos Sobral Sousa, Aurora Felice Castro Issa, Bruno Ramos Nascimento, Harry Correa Filho, Marcelo Luiz Campos Vieira
    Norms and Guidelines Coordinator: Brivaldo Markman Filho
    *Supplemental Materials
    For additional information, please click here .
  • Erratum

    October 2019 Issue, vol. 113 (4), pages 787-891
    In the “Updated Cardiovascular Prevention Guideline of the Brazilian Society of Cardiology – 2019”, with DOI: https://doi.org/10.5935/abc.20190204, published in the journal Arquivos Brasileiros de Cardiologia, on page 862, correct item “Non-HDL-cholesterol” in table 11.3, “> 145” to “<145”, in columns 1 and 2; on page 863, correct the item “Non-HDL-cholesterol”, in Lipids, from table 11.6, “> 145” to “< 145”, in columns 1 and 2.
    January 2021 Issue, vol. 116 (1), pages 160-212
    In the “Position Statement on Fat Consumption and Cardiovascular Health – 2020”, with DOI: https://doi.org/10.36660/abc.20201340, published in the journal Arquivos Brasileiros de Cardiologia, 116(1):160-212, on page 160, correct author name Lis Mie Misuzawa Beda to: Lis Mie Masuzawa Beda.

Publication Dates

  • Publication in this collection
    27 Jan 2021
  • Date of issue
    Jan 2021
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