Dietary linoleic acid and human health: Focus on cardiovascular and cardiometabolic effects


      • Linoleic acid (LA) is an essential18-carbon n-6 polyunsaturated fatty acid.
      • An adequate dietary supply of LA is crucial for human health.
      • LA intakes/blood levels are inversely correlated with cardiovascular disease risk.
      • LA intakes should be increased in most western countries.


      This narrative review aims to discuss the more relevant evidence on the role of linoleic acid (LA), a n-6 essential fatty acid that constitutes the predominant proportion of dietary polyunsaturated fatty acids (PUFA), in cardiovascular health. Although LA can be metabolized into Arachidonic Acid (AA), a 20 carbon PUFA which is the precursor of eicosanoids, including some with proinflammatory or prothrombotic-vasoconstrictor action, the large majority of experimental and clinical studies have assessed the potential benefit of increasing dietary intake of LA. Overall, data from clinical studies and meta-analyses suggest an association between high dietary intakes or tissue levels of n-6 PUFA, and specifically LA, and the improvement of cardiovascular risk (mainly of the plasma lipid profile), as well as long-term glycaemic control and insulin resistance. Most observational data show that elevated/increased dietary intake or tissue levels of LA is associated with a reduced incidence of cardiovascular diseases (mainly coronary artery diseases) and of new onset metabolic syndrome or type 2 diabetes. The effects of LA (or n-6 PUFA) in other physio-pathological areas are less clear. High quality clinical trials are needed to assess both the actual amplitude and the underlying mechanisms of the health effects related to dietary intake of this essential fatty acid.

      Graphical abstract


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Atherosclerosis
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Benjamin E.J.
        • Blaha M.J.
        • Chiuve S.E.
        • et al.
        Heart disease and stroke statistics-2017 update: a report from the American heart association.
        Circulation. 2017; 135: e146-e603
        • Pan A.
        • Lin X.
        • Hemler E.
        • et al.
        Diet and cardiovascular disease: advances and challenges in population-based studies.
        Cell Metabol. 2018; 27: 489-496
        • Meier T.
        • Grafe K.
        • Senn F.
        • et al.
        Cardiovascular mortality attributable to dietary risk factors in 51 countries in the WHO European Region from 1990 to 2016: a systematic analysis of the Global Burden of Disease Study.
        Eur. J. Epidemiol. 2019; 34: 37-55
        • 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: 1958-1972
        • Wang Q.
        • Afshin A.
        • Yakoob M.Y.
        • et al.
        Impact of nonoptimal intakes of saturated, polyunsaturated, and trans fat on global burdens of coronary heart disease.
        J Am Heart Assoc. 2016; 5
        • Zhang J.Y.
        • Kothapalli K.S.
        • Brenna J.T.
        Desaturase and elongase-limiting endogenous long-chain polyunsaturated fatty acid biosynthesis.
        Curr. Opin. Clin. Nutr. Metab. Care. 2016; 19: 103-110
        • EFSA Panel on Dietetic Products
        Nutrition and Allergies (NDA), Scientific Opinion on the substantiation of health claims related to linoleic acid and maintenance of normal blood cholesterol concentrations (ID 489) pursuant to Article 13(1) of Regulation (EC) No 1924/2006 on request from the European Commission.
        EFSA J. 2009; 7: 1276
        • Sonnweber T.
        • Pizzini A.
        • Nairz M.
        • et al.
        Arachidonic acid metabolites in cardiovascular and metabolic diseases.
        Int. J. Mol. Sci. 2018; 19
        • Russo G.L.
        Dietary n-6 and n-3 polyunsaturated fatty acids: from biochemistry to clinical implications in cardiovascular prevention.
        Biochem. Pharmacol. 2009; 77: 937-946
        • Harris W.S.
        Linoleic Acid and Coronary Heart Disease, Prostaglandins, Leukotrienes, and Essential Fatty Acids. vol 79. 2008: 169-171
        • 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; 7e1000252
        • Mensink R.P.
        Effects of Saturated Fatty Acids on Serum Lipids and Lipoproteins: A Systematic Review and Regression Analysis.
        World Health Organization, Geneva2016
        • Bjermo H.
        • Iggman D.
        • Kullberg J.
        • et al.
        Effects of n-6 PUFAs compared with SFAs on liver fat, lipoproteins, and inflammation in abdominal obesity: a randomized controlled trial.
        Am. J. Clin. Nutr. 2012; 95: 1003-1012
        • Imamura F.
        • Fretts A.
        • Marklund M.
        • et al.
        Fatty acid biomarkers of dairy fat consumption and incidence of type 2 diabetes: a pooled analysis of prospective cohort studies.
        PLoS Med. 2018; 15e1002670
        • Burr G.O.
        • Burr M.M.
        On the nature and role of the fatty acids essential in nutrition.
        J. Biol. Chem. 1930; 86: 587-621
        • Plourde M.
        • Cunnane S.C.
        Extremely limited synthesis of long chain polyunsaturates in adults: implications for their dietary essentiality and use as supplements.
        Appl. Physiol. Nutr. Metabol. 2007; 32: 619-634
        • Lauritzen L.
        • Fewtrell M.
        • Agostoni C.
        Dietary arachidonic acid in perinatal nutrition: a commentary.
        Pediatr. Res. 2015; 77: 263-269
        • Brenna J.T.
        Arachidonic acid needed in infant formula when docosahexaenoic acid is present.
        Nutr. Rev. 2016; 74: 329-336
        • Spector A.A.
        • Kaduce T.L.
        • Hoak J.C.
        • et al.
        Utilization of arachidonic and linoleic acids by cultured human endothelial cells.
        J. Clin. Investig. 1981; 68: 1003-1011
        • Risé P.
        • Ghezzi S.
        • Priori I.
        • et al.
        Differential modulation by simvastatin of the metabolic pathways in the n-9, n-6 and n-3 fatty acid series, in human monocytic and hepatocytic cell lines.
        Biochem. Pharmacol. 2005; 69: 1095-1100
        • Moore S.A.
        • Yoder E.
        • Murphy S.
        • et al.
        Astrocytes, not neurons, produce docosahexaenoic acid (22:6 omega-3) and arachidonic acid (20:4 omega-6).
        J. Neurochem. 1991; 56: 518-524
        • Whelan J.
        • Fritsche K.
        Linoleic acid.
        Adv. Nutr. 2013; 4: 311-312
        • Rett B.S.
        • Whelan J.
        Increasing dietary linoleic acid does not increase tissue arachidonic acid content in adults consuming Western-type diets: a systematic review.
        Nutr. Metab. 2011; 8: 36
        • Adam O.
        • Wolfram G.
        • Zollner N.
        Influence of dietary linoleic acid intake with different fat intakes on arachidonic acid concentrations in plasma and platelet lipids and eicosanoid biosynthesis in female volunteers.
        Ann. Nutr. Metab. 2003; 47: 31-36
        • Das U.N.
        Essential fatty acids: biochemistry, physiology and pathology.
        Biotechnol. J. 2006; 1: 420-439
        • Nakamura M.T.
        • Nara T.Y.
        Gene regulation of mammalian desaturases.
        Biochem. Soc. Trans. 2002; 30: 1076-1079
        • Marangoni F.
        • Colombo C.
        • De Angelis L.
        • et al.
        Cigarette smoke negatively and dose-dependently affects the biosynthetic pathway of the n-3 polyunsaturated fatty acid series in human mammary epithelial cells.
        Lipids. 2004; 39: 633-637
        • Simon J.A.
        • Fong J.
        • Bernert Jr., J.T.
        • et al.
        Relation of smoking and alcohol consumption to serum fatty acids.
        Am. J. Epidemiol. 1996; 144: 325-334
        • Pawlosky R.
        • Hibbeln J.
        • Wegher B.
        • et al.
        The effects of cigarette smoking on the metabolism of essential fatty acids.
        Lipids. 1999; 34: S287
        • Risé P.
        • Eligini S.
        • Ghezzi S.
        • et al.
        Fatty acid composition of plasma, blood cells and whole blood: relevance for the assessment of the fatty acid status in humans.
        Prostaglandins Leukot. Essent. Fatty Acids. 2007; 76: 363-369
        • Skeaff C.M.
        • Hodson L.
        • McKenzie J.E.
        Dietary-induced changes in fatty acid composition of human plasma, platelet, and erythrocyte lipids follow a similar time course.
        J. Nutr. 2006; 136: 565-569
        • Risé P.
        • Tragni E.
        • Ghezzi S.
        • et al.
        Different patterns characterize Omega 6 and Omega 3 long chain polyunsaturated fatty acid levels in blood from Italian infants, children, adults and elderly.
        Prostaglandins Leukot. Essent. Fatty Acids. 2013; 89: 215-220
        • Schaeffer L.
        • Gohlke H.
        • Muller M.
        • et al.
        Common genetic variants of the FADS1 FADS2 gene cluster and their reconstructed haplotypes are associated with the fatty acid composition in phospholipids.
        Hum. Mol. Genet. 2006; 15: 1745-1756
        • Lattka E.
        • Illig T.
        • Koletzko B.
        • et al.
        Genetic variants of the FADS1 FADS2 gene cluster as related to essential fatty acid metabolism.
        Curr. Opin. Lipidol. 2010; 21: 64-69
        • Koletzko B.
        Human milk lipids.
        Ann. Nutr. Metab. 2016; 69: 28-40
        • Crawford M.A.
        • Costeloe K.
        • Ghebremeskel K.
        • et al.
        Are deficits of arachidonic and docosahexaenoic acids responsible for the neural and vascular complications of preterm babies?.
        Am. J. Clin. Nutr. 1997; 66: 1032S-1041S
        • Guyenet S.J.
        • Carlson S.E.
        Increase in adipose tissue linoleic acid of US adults in the last half century.
        Adv Nutr. 2015; 6: 660-664
        • Raatz S.K.
        • Conrad Z.
        • Jahns L.
        Trends in linoleic acid intake in the United States adult population: NHANES 1999-2014.
        Prostaglandins, Leukot. Essent. Fatty Acids. 2018; 133: 23-28
        • de Lorgeril M.
        • Salen P.
        New insights into the health effects of dietary saturated and omega-6 and omega-3 polyunsaturated fatty acids.
        BMC Med. 2012; 10: 50
        • FAO
        Food-based dietary guidelines.
        • Institute of Medicine
        Otten J.J. Hellwig J.P. Meyers L.D. Dietary Reference Intakes. The Essential Guide to Nutrient Requirements. THE NATIONAL ACADEMIES PRESS, Washington, D.C.2006
        • EFSA Panel on Dietetic Products Nutrition and Allergies (NDA)
        Scientific Opinion on Dietary Reference Values for fats, including saturated fatty acids, polyunsaturated fatty acids, monounsaturated fatty acids, trans fatty acids, and cholesterol.
        EFSA J. 2010; 8: 1461
        • Harris W.S.
        • Mozaffarian D.
        • Rimm E.
        • et al.
        Omega-6 fatty acids and risk for cardiovascular disease: a science advisory from the American heart association nutrition subcommittee of the council on nutrition, physical activity, and metabolism; council on cardiovascular nursing; and council on epidemiology and prevention.
        Circulation. 2009; 119: 902-907
        • Slavin J.
        Dietary guidelines.
        Nutr Today. 2012; 47: 245-251
        • Brink E.
        • Postma-Smeets A.
        • Stafleu A.
        • et al.
        The Wheel of Five.
        Den Haag, 2015
      1. Dietary Reference Values for Nutrients Summary Report. EFSA Supporting Publications, 2017e15121
        • Società Italiana di Nutrizione Umana (SINU)
        SICS LARN, Livelli Di Assunzione Di Riferimento Di Nutrienti Ed Energia Per La Popolazione Italiana. 2014
        • Nordic Council of Ministers
        Nordic Nutrition Recommendations 2012.
        fifth ed. Narayana Press, 2014
        • ANSES
        Actualisation des apports nutritionnels conseillés pour les acides gras.
        • FAO
        Fats and Fatty Acids in Human Nutrition. Report of an Expert Consultation.
        vol 91. FAO Food Nutr Pap, 2010: 1-166
        • Clarke R.
        • Frost C.
        • Collins R.
        • et al.
        Dietary lipids and blood cholesterol: quantitative meta-analysis of metabolic ward studies.
        BMJ. 1997; 314: 112-117
        • Hooper L.
        • Al-Khudairy L.
        • Abdelhamid A.S.
        • et al.
        Omega-6 fats for the primary and secondary prevention of cardiovascular disease.
        Cochrane Database Syst. Rev. 2018; 11: CD011094
        • Maki K.C.
        • Lawless A.L.
        • Kelley K.M.
        • et al.
        Corn oil improves the plasma lipoprotein lipid profile compared with extra-virgin olive oil consumption in men and women with elevated cholesterol: results from a randomized controlled feeding trial.
        J Clin Lipidol. 2015; 9: 49-57
        • Maki K.C.
        • Hasse W.
        • Dicklin M.R.
        • 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: 1556-1563
        • Cicero A.F.G.
        • d'Addato S.
        • Fiorito A.
        • et al.
        Plasma lipid effects of corn oil and extra-virgin olive oil in hypercholesterolaemic subjects: a randomised, controlled trial.
        Mediterr. J. Nutr. Metab. 2009; 1: 187-192
        • Mustad V.A.
        • Ellsworth J.L.
        • Cooper A.D.
        • 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: 2310-2323
        • Yoshikawa T.
        • Shimano H.
        • Yahagi N.
        • et al.
        Polyunsaturated fatty acids suppress sterol regulatory element-binding protein 1c promoter activity by inhibition of liver X receptor (LXR) binding to LXR response elements.
        J. Biol. Chem. 2002; 277: 1705-1711
        • Iggman D.
        • Rosqvist F.
        • Larsson A.
        • et al.
        Role of dietary fats in modulating cardiometabolic risk during moderate weight gain: a randomized double-blind overfeeding trial (LIPOGAIN study).
        J Am Heart Assoc. 2014; 3e001095
        • Drouin-Chartier J.P.
        • Tremblay A.J.
        • Lepine M.C.
        • et al.
        Substitution of dietary omega-6 polyunsaturated fatty acids for saturated fatty acids decreases LDL apolipoprotein B-100 production rate in men with dyslipidemia associated with insulin resistance: a randomized controlled trial.
        Am. J. Clin. Nutr. 2018; 107: 26-34
        • Iacono J.M.
        • Dougherty R.M.
        • Puska P.
        Reduction of blood pressure associated with dietary polyunsaturated fat.
        Hypertension. 1982; 4: III34-42
        • Mutanen M.
        • Kleemola P.
        • Valsta L.M.
        • et al.
        Lack of effect on blood pressure by polyunsaturated and monounsaturated fat diets.
        Eur. J. Clin. Nutr. 1992; 46: 1-6
        • Mensink R.P.
        • Janssen M.C.
        • Katan M.B.
        Effect on blood pressure of two diets differing in total fat but not in saturated and polyunsaturated fatty acids in healthy volunteers.
        Am. J. Clin. Nutr. 1988; 47: 976-980
        • Zock P.L.
        • Blijlevens R.A.
        • de Vries J.H.
        • et al.
        Effects of stearic acid and trans fatty acids versus linoleic acid on blood pressure in normotensive women and men.
        Eur. J. Clin. Nutr. 1993; 47: 437-444
        • Aro A.
        • Pietinen P.
        • Valsta L.M.
        • et al.
        Lack of effect on blood pressure by low fat diets with different fatty acid compositions.
        J. Hum. Hypertens. 1998; 12: 383-389
        • Miura K.
        • Stamler J.
        • Nakagawa H.
        • et al.
        Relationship of dietary linoleic acid to blood pressure. The International Study of Macro-Micronutrients and Blood Pressure Study [corrected].
        Hypertension. 2008; 52: 408-414
        • Wang L.
        • Manson J.E.
        • Forman J.P.
        • et al.
        Dietary fatty acids and the risk of hypertension in middle-aged and older women.
        Hypertension. 2010; 56: 598-604
        • Gaschler M.M.
        • Stockwell B.R.
        Lipid peroxidation in cell death.
        Biochem. Biophys. Res. Commun. 2017; 482: 419-425
        • Giordano E.
        • Visioli F.
        Long-chain omega 3 fatty acids: molecular bases of potential antioxidant actions.
        Prostaglandins Leukot. Essent. Fatty Acids. 2014; 90: 1-4
        • de Kok T.M.
        • Zwingman I.
        • Moonen E.J.
        • et al.
        Analysis of oxidative DNA damage after human dietary supplementation with linoleic acid.
        Food Chem. Toxicol. : Int. . Publ. Br. Ind. Biol. Res. Assoc. 2003; 41: 351-358
        • Koenig W.
        Inflammation revisited: atherosclerosis in the post-CANTOS era.
        European cardiology. 2017; 12: 89-91
        • Calder P.C.
        • Bosco N.
        • Bourdet-Sicard R.
        • et al.
        Health relevance of the modification of low grade inflammation in ageing (inflammageing) and the role of nutrition.
        Ageing Res. Rev. 2017; 40: 95-119
        • Bersch-Ferreira A.C.
        • Sampaio G.R.
        • Gehringer M.O.
        • et al.
        Association between polyunsaturated fatty acids and inflammatory markers in patients in secondary prevention of cardiovascular disease.
        Nutrition. 2017; 37: 30-36
        • Bersch-Ferreira A.C.
        • Sampaio G.R.
        • Gehringer M.O.
        • et al.
        Association between plasma fatty acids and inflammatory markers in patients with and without insulin resistance and in secondary prevention of cardiovascular disease, a cross-sectional study.
        Nutr. J. 2018; 17: 26
        • Ferrucci L.
        • Cherubini A.
        • Bandinelli S.
        • et al.
        Relationship of plasma polyunsaturated fatty acids to circulating inflammatory markers.
        J. Clin. Endocrinol. Metab. 2006; 91: 439-446
        • 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. (N.Y.). 2009; 29: 363-370
        • Muka T.
        • Kiefte-de Jong J.C.
        • Hofman A.
        • et al.
        Polyunsaturated fatty acids and serum C-reactive protein: the Rotterdam study.
        Am. J. Epidemiol. 2015; 181: 846-856
        • Gonzalez-Gil E.M.
        • Santabarbara J.
        • Siani A.
        • et al.
        Whole-blood fatty acids and inflammation in European children: the IDEFICS Study.
        Eur. J. Clin. Nutr. 2016; 70: 819-823
        • Johnson G.H.
        • Fritsche K.
        Effect of dietary linoleic acid on markers of inflammation in healthy persons: a systematic review of randomized controlled trials.
        J. Acad. Nutr. Diet. 2012; 112: 1029-1041.e15
        • Kelley D.S.
        • Taylor P.C.
        • Nelson G.J.
        • et al.
        Arachidonic acid supplementation enhances synthesis of eicosanoids without suppressing immune functions in young healthy men.
        Lipids. 1998; 33: 125-130
        • Kakutani S.
        • Ishikura Y.
        • Tateishi N.
        • et al.
        Supplementation of arachidonic acid-enriched oil increases arachidonic acid contents in plasma phospholipids, but does not increase their metabolites and clinical parameters in Japanese healthy elderly individuals: a randomized controlled study.
        Lipids Health Dis. 2011; 10: 241
        • Lankinen M.A.
        • Fauland A.
        • Shimizu B.I.
        • et al.
        Inflammatory response to dietary linoleic acid depends on FADS1 genotype.
        Am. J. Clin. Nutr. 2019; 109: 165-175
        • Innes J.K.
        • Calder P.C.
        Omega-6 fatty acids and inflammation.
        Prostaglandins Leukot. Essent. Fatty Acids. 2018; 132: 41-48
        • Silva J.R.
        • Burger B.
        • Kuhl C.M.C.
        • et al.
        Wound Healing and Omega-6 Fatty Acids: From Inflammation to Repair. 2018. Mediators Inflamm, 2018
        • Fritsche K.L.
        Too much linoleic acid promotes inflammation-doesn't it?.
        Prostaglandins Leukot. Essent. Fatty Acids. 2008; 79: 173-175
        • Naughton S.S.
        • Mathai M.L.
        • Hryciw D.H.
        • et al.
        Linoleic acid and the pathogenesis of obesity.
        Prostaglandins Other Lipid Mediat. 2016; 125: 90-99
        • Steffen L.M.
        • Vessby B.
        • Jacobs Jr., D.R.
        • et al.
        Serum phospholipid and cholesteryl ester fatty acids and estimated desaturase activities are related to overweight and cardiovascular risk factors in adolescents.
        Int. J. Obes. 2008; 32: 1297-1304
        • Pickens C.A.
        • Sordillo L.M.
        • Comstock S.S.
        • et al.
        Plasma phospholipids, non-esterified plasma polyunsaturated fatty acids and oxylipids are associated with BMI.
        Prostaglandins Leukot. Essent. Fatty Acids. 2015; 95: 31-40
        • Fekete K.
        • Gyorei E.
        • Lohner S.
        • et al.
        Long-chain polyunsaturated fatty acid status in obesity: a systematic review and meta-analysis.
        Obes. Rev. : Off. J. Int. Assoc. Stud. Obesity. 2015; 16: 488-497
        • Williams E.S.
        • Baylin A.
        • Campos H.
        Adipose tissue arachidonic acid and the metabolic syndrome in Costa Rican adults.
        Clin. Nutr. 2007; 26: 474-482
        • Li K.
        • Brennan L.
        • Bloomfield J.F.
        • et al.
        Adiposity associated plasma linoleic acid is related to demographic, metabolic health and haplotypes of FADS1/2 genes in Irish adults.
        Mol. Nutr. Food Res. 2018; 62e1700785
        • Yary T.
        • Voutilainen S.
        • Tuomainen T.P.
        • et al.
        Omega-6 polyunsaturated fatty acids, serum zinc, delta-5- and delta-6-desaturase activities and incident metabolic syndrome.
        J. Hum. Nutr. Diet. : Off. J. Br. Diet. Assoc. 2017; 30: 506-514
        • Bonafini S.
        • Tagetti A.
        • Gaudino R.
        • et al.
        Individual fatty acids in erythrocyte membranes are associated with several features of the metabolic syndrome in obese children.
        Eur. J. Nutr. 2019; 58: 731-742
        • Liu X.
        • Li Y.
        • Tobias D.K.
        • et al.
        Changes in types of dietary fats influence long-term weight change in US women and men.
        J. Nutr. 2018; 148: 1821-1829
        • NCD Risk Factor Collaboration (NCD-RisC)
        Worldwide trends in diabetes since 1980: a pooled analysis of 751 population-based studies with 4.4 million participants.
        Lancet. 2016; 387: 1513-1530
        • Evert A.B.
        • Boucher J.L.
        • Cypress M.
        • et al.
        Nutrition therapy recommendations for the management of adults with diabetes.
        Diabetes Care. 2013; 36: 3821-3842
        • Wu J.H.Y.
        • Marklund M.
        • Imamura F.
        • et al.
        Omega-6 fatty acid biomarkers and incident type 2 diabetes: pooled analysis of individual-level data for 39 740 adults from 20 prospective cohort studies.
        Lancet Diabetes Endocrinol. 2017; 5: 965-974
        • Riserus U.
        • Willett W.C.
        • Hu F.B.
        Dietary fats and prevention of type 2 diabetes.
        Prog. Lipid Res. 2009; 48: 44-51
        • Vessby B.
        • Aro A.
        • Skarfors E.
        • et al.
        The risk to develop NIDDM is related to the fatty acid composition of the serum cholesterol esters.
        Diabetes. 1994; 43: 1353-1357
        • Meyer K.A.
        • Kushi L.H.
        • Jacobs Jr., D.R.
        • et al.
        Dietary fat and incidence of type 2 diabetes in older Iowa women.
        Diabetes Care. 2001; 24: 1528-1535
        • Harding A.H.
        • Day N.E.
        • Khaw K.T.
        • et al.
        Dietary fat and the risk of clinical type 2 diabetes: the European prospective investigation of Cancer-Norfolk study.
        Am. J. Epidemiol. 2004; 159: 73-82
        • Imamura F.
        • Micha R.
        • Wu J.H.
        • et al.
        Effects of saturated fat, polyunsaturated fat, monounsaturated fat, and carbohydrate on glucose-insulin homeostasis: a systematic review and meta-analysis of randomised controlled feeding trials.
        PLoS Med. 2016; 13e1002087
        • Mahendran Y.
        • Agren J.
        • Uusitupa M.
        • et al.
        Association of erythrocyte membrane fatty acids with changes in glycemia and risk of type 2 diabetes.
        Am. J. Clin. Nutr. 2014; 99: 79-85
        • Badoud F.
        • Lam K.P.
        • Perreault M.
        • et al.
        Metabolomics reveals metabolically healthy and unhealthy obese individuals differ in their response to a caloric challenge.
        PLoS One. 2015; 10e0134613
        • Nemati R.
        • Lu J.
        • Tura A.
        • et al.
        Acute changes in non-esterified fatty acids in patients with type 2 diabetes receiving bariatric surgery.
        Obes. Surg. 2017; 27: 649-656
        • Salas-Salvado J.
        • Bullo M.
        • Babio N.
        • et al.
        Reduction in the incidence of type 2 diabetes with the Mediterranean diet: results of the PREDIMED-Reus nutrition intervention randomized trial.
        Diabetes Care. 2011; 34: 14-19
        • Wanders A.J.
        • Blom W.A.M.
        • Zock P.L.
        • et al.
        Plant-derived polyunsaturated fatty acids and markers of glucose metabolism and insulin resistance: a meta-analysis of randomized controlled feeding trials.
        BMJ Open Diabetes Res. Care. 2019; 7e000585
        • Riccardi G.
        • Giacco R.
        • Rivellese A.A.
        Dietary fat, insulin sensitivity and the metabolic syndrome.
        Clin. Nutr. 2004; 23: 447-456
        • Farvid M.S.
        • 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: 1568-1578
        • Jakobsen M.U.
        • O'Reilly E.J.
        • Heitmann B.L.
        • 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: 1425-1432
        • Wang D.D.
        • Li Y.
        • Chiuve S.E.
        • et al.
        Association of specific dietary fats with total and cause-specific mortality.
        JAMA Int. Med. 2016; 176: 1134-1145
        • Marklund M.
        • Wu J.H.Y.
        • Imamura F.
        • et al.
        Biomarkers of dietary omega-6 fatty acids and incident cardiovascular disease and mortality: an individual-level pooled analysis of 30 cohort studies.
        Circulation. 2019; 139: 2422-2436
        • Block R.C.
        • Harris W.S.
        • Reid K.J.
        • et al.
        Omega-6 and trans fatty acids in blood cell membranes: a risk factor for acute coronary syndromes?.
        Am. Heart J. 2008; 156: 1117-1123
        • Marangoni F.
        • Novo G.
        • Perna G.
        • et al.
        Omega-6 and omega-3 polyunsaturated fatty acid levels are reduced in whole blood of Italian patients with a recent myocardial infarction: the AGE-IM study.
        Atherosclerosis. 2014; 232: 334-338
        • De Goede J.
        • Verschuren W.M.
        • Boer J.M.
        • et al.
        N-6 and n-3 fatty acid cholesteryl esters in relation to incident stroke in a Dutch adult population: a nested case-control study, Nutrition, metabolism, and cardiovascular diseases.
        Nutr. Metab. Cardiovasc. Dis. 2013; 23: 737-743
        • Iso H.
        • Sato S.
        • Umemura U.
        • et al.
        Linoleic acid, other fatty acids, and the risk of stroke.
        Stroke. 2002; 33: 2086-2093
        • Yaemsiri S.
        • Sen S.
        • Tinker L.F.
        • et al.
        Serum fatty acids and incidence of ischemic stroke among postmenopausal women.
        Stroke. 2013; 44: 2710-2717
        • Wu J.H.
        • Lemaitre R.N.
        • King I.B.
        • et al.
        Circulating omega-6 polyunsaturated fatty acids and total and cause-specific mortality: the Cardiovascular Health Study.
        Circulation. 2014; 130: 1245-1253
        • Delgado G.E.
        • Marz W.
        • Lorkowski S.
        • et al.
        Omega-6 fatty acids: opposing associations with risk-the ludwigshafen risk and cardiovascular health study.
        J. Clin. Lipidol. 2017; 11 (e1014): 1082-1090
        • Sacks F.M.
        • Lichtenstein A.H.
        • Wu J.H.Y.
        • et al.
        Dietary fats and cardiovascular disease: a presidential advisory from the American heart association.
        Circulation. 2017; 136: e1-e23
        • Virtanen J.K.
        • Wu J.H.Y.
        • Voutilainen S.
        • et al.
        Serum n-6 polyunsaturated fatty acids and risk of death: the Kuopio Ischaemic heart disease risk factor study.
        Am. J. Clin. Nutr. 2018; 107: 427-435
        • de Oliveira Otto M.C.
        • Wu J.H.
        • Baylin A.
        • et al.
        Circulating and dietary omega-3 and omega-6 polyunsaturated fatty acids and incidence of CVD in the Multi-Ethnic Study of Atherosclerosis.
        J. Am. Heart Assoc. 2013; 2e000506
        • Hamley S.
        The effect of replacing saturated fat with mostly n-6 polyunsaturated fat on coronary heart disease: a meta-analysis of randomised controlled trials.
        Nutr. J. 2017; 16: 30
        • Harris W.S.
        • Shearer G.C.
        Omega-6 fatty acids and cardiovascular disease: friend, not foe?.
        Circulation. 2014; 130: 1562-1564
        • Ramsden C.E.
        • Zamora D.
        • Majchrzak-Hong S.
        • et al.
        Re-evaluation of the traditional diet-heart hypothesis: analysis of recovered data from Minnesota Coronary Experiment (1968-73).
        BMJ. 2016; 353: i1246
        • Stanley J.C.
        • Elsom R.L.
        • Calder P.C.
        • et al.
        UK Food Standards Agency Workshop Report: the effects of the dietary n-6:n-3 fatty acid ratio on cardiovascular health.
        Br. J. Nutr. 2007; 98: 1305-1310
        • Zhuang P.
        • Zhang Y.
        • He W.
        • et al.
        Dietary fats in relation to total and cause-specific mortality in a prospective cohort of 521 120 individuals with 16 Years of follow-up.
        Circ. Res. 2019; 124: 757-768
        • Maki K.C.
        • Eren F.
        • Cassens M.E.
        • et al.
        omega-6 polyunsaturated fatty acids and cardiometabolic health: current evidence, controversies, and research gaps.
        Adv. Nutr. 2018; 9: 688-700