Advertisement

Omega-6 fatty acids and inflammation

  • Jacqueline K. Innes
    Affiliations
    Human Development and Health Academic Unit, Faculty of Medicine, University of Southampton, IDS Building, MP887 Southampton General Hospital, Tremona Road, Southampton SO16 6YD, United Kingdom
    Search for articles by this author
  • Philip C. Calder
    Correspondence
    Corresponding author at: Human Development and Health Academic Unit, Faculty of Medicine, University of Southampton, IDS Building, MP887 Southampton General Hospital, Tremona Road, Southampton SO16 6YD, United Kingdom.
    Affiliations
    Human Development and Health Academic Unit, Faculty of Medicine, University of Southampton, IDS Building, MP887 Southampton General Hospital, Tremona Road, Southampton SO16 6YD, United Kingdom

    National Institute for Health Research Southampton Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust and University of Southampton, Southampton SO16 6YD, United Kingdom
    Search for articles by this author

      Highlights

      • There is a high content of omega-6 PUFAs, particularly arachidonic acid, in membranes of cells involved in inflammation.
      • High omega-6 PUFA dietary intake has been linked to inflammation, mainly because ARA is the precursor of pro-inflammatory lipid mediators.
      • However, some studies have shown that increased dietary intake of omega-6 PUFAs may not lead to enhanced inflammation.
      • This article investigates the extent to which omega-6 PUFAs are involved in the inflammatory process.

      Abstract

      Inflammation is a normal process that is part of host defence and tissue healing. However, excessive or unresolved inflammation can lead to uncontrolled tissue damage, pathology and disease. In humans on a Western diet, the omega-6 polyunsaturated fatty acid arachidonic acid (ARA) makes a significant contribution to the fatty acids present in the membrane phospholipids of cells involved in inflammation. ARA is a precursor to a number of potent pro-inflammatory mediators including well described prostaglandins and leukotrienes, which has led to the development of anti-inflammatory pharmaceuticals that target the ARA pathway to successfully control inflammation. Hence, it is commonly believed that increasing dietary intake of the omega-6 fatty acids ARA or its precursor linoleic acid (LA) will increase inflammation. However, studies in healthy human adults have found that increased intake of ARA or LA does not increase the concentrations of many inflammatory markers. Epidemiological studies have even suggested that ARA and LA may be linked to reduced inflammation. Contrastingly, there is also evidence that a high omega-6 fatty acid diet inhibits the anti-inflammatory and inflammation-resolving effect of the omega-3 fatty acids. Thus, the interaction of omega-3 and omega-6 fatty acids and their lipid mediators in the context of inflammation is complex and still not properly understood.

      Keywords

      Abbreviations:

      ARA (arachidonic acid), ARASCO (arachidonic acid-rich single-cell oil), COX (cyclooxygenase), CRP (C-reactive protein), DGLA (dihomo-gamma-linolenic acid), DHA (docosahexaenoic acid), EPA (eicosapentaenoic acid), GLA (gamma-linolenic acid), HETE (hydroxyeicosatetraenoic acid), HODE (hydroxyoctadecadienoic acid), IL (interleukin), LA (linoleic acid), LOX (lipoxygenase), LPS (lipopolysaccharide), LT (leukotriene), LXA4 (lipoxin A4), NF-kB (nuclear factor kappa B), PBMC (peripheral blood mononuclear cell), PG (prostaglandin), PMN (polymorphonuclear neutrophil), PPAR (peroxisome proliferator-activated receptor), PUFA (polyunsaturated fatty acid), sE-selectin (soluble E-selectin), sICAM-1 (soluble intercellular adhesion molecule 1), sTNF-R1 (soluble tumour necrosis factor receptor-1), sVCAM-1 (soluble vascular cell adhesion molecule 1), TGF-β (transforming growth factor β), TNF (tumour necrosis factor), TX (thromboxane)
      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:

      Subscribe to Prostaglandins, Leukotrienes and Essential Fatty Acids
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Calder P.C.
        • Albers R.
        • Antoine J.M.
        • Blum S.
        • Bourdet-Sicard R.
        • Ferns G.A.
        • Folkerts G.
        • Friedmann P.S.
        • Frost G.S.
        • Guarner F.
        • Løvik M.
        • MacFarlane S.
        • Meyer P.D.
        • M'Rabet L.
        • Serafini M.
        • Van Eden W.
        • Van Loo J.
        • Vas Dias W.
        • Vidry S.
        • Winklhofer-Roob B.M.
        • Zhao J.
        Inflammatory disease processes and interactions with nutrition.
        Br. J. Nutr. 2009; 101: S1-S45https://doi.org/10.1017/S0007114509990511
        • Calder P.C.
        • Ahluwalia N.
        • Albers R.
        • Bosco N.
        • Bourdet-Sicard R.
        • Haller D.
        • Holgate S.T.
        • Jönsson L.S.
        • Latulippe M.E.
        • Marcos A.
        • Moreines J.
        • Mrini C.
        • Müller M.
        • Pawelec G.
        • Van Neerven R.J.J.
        • Watzl B.
        • Zhao J.
        A consideration of biomarkers to be used for evaluation of inflammation in human nutritional studies.
        Br. J. Nutr. 2013; 109: S1-S34https://doi.org/10.1017/S0007114512005119
        • Bannenberg G.
        • Serhan C.N.
        Specialized pro-resolving lipid mediators in the inflammatory response: an update.
        Biochim. Biophys. Acta. 2010; 1801: 1260-1273https://doi.org/10.1016/j.bbalip.2010.08.002
        • Serhan C.N.
        • Chiang N.
        • Van Dyke T.E.
        Resolving inflammation: dual anti-inflammatory and pro-resolution lipid mediators.
        Nat. Rev. Immunol. 2008; 8: 349-361https://doi.org/10.1038/nri2294
        • Serhan C.N.
        • Chiang N.
        Resolution phase lipid mediators of inflammation: agonists of resolution.
        Curr. Opin. Pharmacol. 2013; 13: 632-640https://doi.org/10.1016/j.coph.2013.05.012
        • Dalli J.
        • Colas R.A.
        • Serhan C.N.
        Novel n-3 immunoresolvents: structures and actions.
        Sci. Rep. 2013; 3: 1940https://doi.org/10.1038/srep01940
        • Calder P.C.
        • Ahluwalia N.
        • Brouns F.
        • Buetler T.
        • Clement K.
        • Cunningham K.
        • Esposito K.
        • Jönsson L.S.
        • Kolb H.
        • Lansink M.
        • Marcos A.
        • Margioris A.
        • Matusheski N.
        • Nordmann H.
        • O'Brien J.
        • Pugliese G.
        • Rizkalla S.
        • Schalkwijk C.
        • Tuomilehto J.
        • Wärnberg J.
        • Watzl B.
        • Winklhofer-Roob B.M.
        Dietary factors and low-grade inflammation in relation to overweight and obesity.
        Br. J. Nutr. 2011; 106: S5-78https://doi.org/10.1017/S0007114511005460
        • Calder P.C.
        • Bosco N.
        • Bourdet-Sicard R.
        • Capuron L.
        • Delzenne N.
        • Doré J.
        • Franceschi C.
        • Lehtinen M.J.
        • Recker T.
        • Salvioli S.
        • Visioli F.
        Health relevance of the modification of low grade inflammation in ageing (inflammageing) and the role of nutrition.
        Ageing Res. Rev. 2017; 40: 95-119https://doi.org/10.1016/j.arr.2017.09.001
        • Pot G.K.
        • Prynne C.J.
        • Roberts C.
        • Olson A.
        • Nicholson S.K.
        • Whitton C.
        • Teucher B.
        • Bates B.
        • Henderson H.
        • Pigott S.
        • Swan G.
        • Stephen A.M.
        National Diet and Nutrition Survey: fat and fatty acid intake from the first year of the rolling programme and comparison with previous surveys.
        Br. J. Nutr. 2012; 107: 405-415https://doi.org/10.1017/S0007114511002911
        • Blasbalg T.L.
        • Hibbeln J.R.
        • Ramsden C.E.
        • Majchrzak S.F.
        • Rawlings R.R.
        Changes in consumption of omega-3 and omega-6 fatty acids in the United States during the 20th century.
        Am. J. Clin. Nutr. 2011; 93: 950-962https://doi.org/10.3945/ajcn.110.006643.950
        • Forsyth S.
        • Gautier S.
        • Salem Jr., N.
        Global estimates of dietary intake of docosahexaenoic acid and arachidonic acid in developing and developed countries.
        Ann. Nutr. Metab. 2016; 68: 258-267https://doi.org/10.1159/000446855
        • Brenna J.T.
        • Varamini B.
        • Jensen R.G.
        • Diersen-Schade D.A.
        • Boettcher J.A.
        • Arterburn L.M.
        Docosahexaenoic and arachidonic acid concentrations in human breast milk worldwide.
        Am. J. Clin. Nutr. 2007; 85: 1457-1464
        • Calder P.C.
        Fatty acids and inflammation: the cutting edge between food and pharma.
        Eur. J. Pharmacol. 2011; 668: S50-S58https://doi.org/10.1016/j.ejphar.2011.05.085
        • Walker C.G.
        • West A.L.
        • Browning L.M.
        • Madden J.
        • Gambell J.M.
        • Jebb S.A.
        • Calder P.C.
        The pattern of fatty acids displaced by EPA and DHA following 12 months supplementation varies between blood cell and plasma fractions.
        Nutrients. 2015; 7: 6281-6293https://doi.org/10.3390/nu7085285
        • Kew S.
        • Banerjee T.
        • Minihane A.M.
        • Finnegan Y.E.
        • Williams C.M.
        • Calder P.C.
        Relation between the fatty acid composition of peripheral blood mononuclear cells and measures of immune cell function in healthy, free-living subjects aged 25–72 y.
        Am. J. Clin. Nutr. 2003; 77: 1278-1286https://doi.org/10.1093/ajcn/77.5.1278
        • Rees D.
        • Miles E.A.
        • Banerjee T.
        • Wells S.J.
        • Roynette C.E.
        • Wahle K.W.
        • Calder P.C.
        Dose-related effects of eicosapentaenoic acid on innate immune function in healthy humans: a comparison of young and older men.
        Am. J. Clin. Nutr. 2006; 83: 331-342https://doi.org/10.1093/ajcn/83.2.331
        • Yaqoob P.
        • Pala H.S.
        • Cortina-Borja M.
        • Newsholme E.A.
        • Calder P.
        Encapsulated fish oil enriched in alpha-tocopherol alters plasma phospholipid and mononuclear cell fatty acid compositions but not mononuclear cell functions.
        Eur. J. Clin. Invest. 2000; 30: 260-274https://doi.org/10.1046/j.1365-2362.2000.00623.x
        • Thies F.
        • Nebe-von-Caron G.
        • Powell J.R.
        • Yaqoob P.
        • Newsholme E.A.
        • Calder P.C.
        Dietary supplementation with gamma-linolenic acid or fish oil decreases T lymphocyte proliferation in healthy older humans.
        J. Nutr. 2001; 131: 1918-1927
        • Healy D.A.
        • Wallace F.A.
        • Miles E.A.
        • Calder P.C.
        • Newsholme P.
        Effect of low-to-moderate amounts of dietary fish oil on neutrophil lipid composition and function.
        Lipids. 2000; 35: 763-768https://doi.org/10.1007/s11745-000-0583-1
        • Kew S.
        • Mesa M.D.
        • Tricon S.
        • Buckley R.
        • Minihane A.M.
        • Yaqoob P.
        Effects of oils rich in eicosapentaenoic and docosahexaenoic acids on immune cell composition and function in healthy humans.
        Am. J. Clin. Nutr. 2004; 79: 674-681
        • Gibney M.
        • Hunter B.
        The effects of short-and long-term supplementation with fish oil on the incorporation of n-3 polyunsaturated fatty acids into cells of the immune system in healthy volunteers.
        Eur. J. Clin. Nutr. 1993; 47: 255-259
        • Ziboh V.
        • Fletcher M.
        Dose-response effects of dietary γ-linolenic acid-enriched oils on human polymorphonuclear-neutrophil biosynthesis of leukotriene B4.
        Am. J. Clin. Nutr. 1992; 55: 39-45https://doi.org/10.1093/ajcn/55.1.39
        • Sperling R.I.
        • Benincaso A.I.
        • Knoell C.T.
        • Larkin J.K.
        • Austen K.F.
        • Robinson D.R.
        Dietary omega-3 polyunsaturated fatty acids inhibit phosphoinositide formation and chemotaxis in neutrophils.
        J. Clin. Invest. 1993; 91: 651-660https://doi.org/10.1172/JCI116245
        • Dennis E.A.
        Liberating chiral lipid mediators, inflammatory enzymes, and LIPID MAPS from biological grease.
        J. Biol. Chem. 2016; 291: 24431-24448https://doi.org/10.1074/jbc.X116.723791
        • Nicolaou A.
        Prostanoids.
        in: Nicolaou A. Kafatos G. Bioactive Lipids. The Oily Press, Bridgewater2004: 197-222
        • Fiore S.
        Leukotrienes and lipoxins.
        in: Nicolaou A. Kafatos G. Bioactive Lipids. The Oily Press, Bridgewater2004: 223-243
        • Calder P.C.
        Omega-3 polyunsaturated fatty acids and inflammatory processes: nutrition or pharmacology?.
        Br. J. Clin. Pharmacol. 2013; 75: 645-662https://doi.org/10.1111/j.1365-2125.2012.04374.x
        • Tilley S.L.
        • Coffman T.M.
        • Koller B.H.
        Mixed messages: modulation of inflammation and immune responses by prostaglandins and thromboxanes.
        J. Clin. Invest. 2001; 108: 15-23https://doi.org/10.1172/JCI200113416
        • Lewis R.A.
        • Austen K..
        • Soberman R.J.
        Leukotrienes and other products of the 5-lipoxygenase pathway: biochemistry and relation to pathobiology in human diseases.
        N. Engl. J. Med. 1990; 323: 645-655
        • Sano H.
        • Hla T.
        • Maier J.A.M.
        • Crofford L.J.
        • Case J.P.
        • Maciag T.
        • Wilder R.L.
        In vivo cyclooxygenase expression in synovial tissues of patients with rheumatoid arthritis and osteoarthritis and rats with adjuvant and streptococcal cell wall arthritis.
        J. Clin. Invest. 1992; 89: 97-108https://doi.org/10.1172/JCI115591
        • Sperling R.
        Eicosanoids in rheumatoid arthritis.
        Rheum. Dis. Clin. N. Am. 1995; 21: 741-758
        • Masoodi M.
        • Pearl D.S.
        • Eiden M.
        • Shute J.K.
        • Brown J.F.
        • Calder P.C.
        • Trebble T.M.
        Altered colonic mucosal polyunsaturated fatty acid (PUFA) derived lipid mediators in ulcerative colitis: New insight into relationship with disease activity and pathophysiology.
        PLoS One. 2013; 8: 1-13https://doi.org/10.1371/journal.pone.0076532
        • Miles E.A.
        • Allen E.
        • Calder P.C.
        In vitro effects of eicosanoids derived from different 20-carbon fatty acids on production of monocyte-derived cytokines in human whole blood cultures.
        Cytokine. 2002; 20: 215-223https://doi.org/10.1006/cyto.2002.2007
        • Vachier I.
        • Chanez P.
        • Bonnans C.
        • Godard P.
        • Bousquet J.
        • Chavis C.
        Endogenous anti-inflammatory mediators from arachidonate in human neutrophils.
        Biochem. Biophys. Res. Commun. 2002; 290: 219-224https://doi.org/10.1006/bbrc.2001.6155
        • Gewirtz A.T.
        • Collier-Hyams L.S.
        • Young A.N.
        • Kucharzik T.
        • Guilford W.J.
        • Parkinson J.F.
        • Williams I.R.
        • Neish A.S.
        • Madara J.L.
        Lipoxin A4 analogs attenuate induction of intestinal epithelial proinflammatory gene expression and reduce the severity of dextran sodium sulfate-induced colitis.
        J. Immunol. 2002; 168: 5260-5267https://doi.org/10.4049/jimmunol.168.10.5260
        • Levy B.D.
        • Clish C.B.
        • Schmidt B.
        • Gronert K.
        • Serhan C.N.
        Lipid mediator class switching during acute inflammation: signals in resolution.
        Nat. Immunol. 2001; 2: 612-619https://doi.org/10.1038/89759
        • Peterson L.D.
        • Jeffery N.M.
        • Thies F.
        • Sanderson P.
        • Newsholme E.A.
        • Calder P.C.
        Eicosapentaenoic and docosahexaenoic acids alter rat spleen leukocyte fatty acid composition and prostaglandin E2 production but have different effects on lymphocyte functions and cell-mediated immunity.
        Lipids. 1998; 33: 171-180https://doi.org/10.1007/s11745-998-0193-y
        • Kelley D.S.
        • Taylor P.C.
        • Nelson G.J.
        • Mackey B.E.
        Arachidonic acid supplementation enhances synthesis of eicosanoids without suppressing immune functions in young healthy men.
        Lipids. 1998; 33: 125-130https://doi.org/10.1007/s11745-998-0187-9
        • Thies F.
        • Miles E.A.
        • Nebe-von-Caron G.
        • Powell J.R.
        • Hurst T.L.
        • Newsholme E.A.
        • Calder P.C.
        Influence of dietary supplementation with long-chain n-3 or n-6 polyunsaturated fatty acids on blood inflammatory cell populations and functions and on plasma soluble adhesion molecules in healthy adults.
        Lipids. 2001; 36: 1183-1193https://doi.org/10.1007/s11745-001-0831-4
        • Kakutani S.
        • Ishikura Y.
        • Tateishi N.
        • Horikawa C.
        • Tokuda H.
        • Kontani M.
        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: 1-12https://doi.org/10.1186/1476-511X-10-241
        • Chilton-Lopez T.
        • Surette M.E.
        • Swan D.D.
        • Fonteh A.N.
        • Johnson M.M.
        • Chilton F.H.
        Metabolism of gammalinolenic acid in human neutrophils.
        J. Immunol. 1996; 156: 2941-2947
        • Johnson M.
        • Swan D.
        • Surette M.
        • Stegner J.
        • Chilton T.
        • Fonteh A.
        • Chilton F.
        Dietary supplementation with gamma-linolenic acid alters fatty acid content and eicosanoid production in healthy humans.
        J. Nutr. 1997; 127: 1435-1444https://doi.org/10.1093/jn/127.8.1435
        • Ziboh V.A.
        • Naguwa S.
        • Vang K.
        • Wineinger J.
        • Morrissey B.M.
        • Watnik M.
        • Gershwin M.E.
        Suppression of leukotriene B4 generation by ex-vivo neutrophils isolated from asthma patients on dietary supplementation with gammalinolenic acid-containing borage oil: Possible implication in asthma.
        Clin. Dev. Immunol. 2004; 11: 13-21https://doi.org/10.1080/10446670410001670445
        • Sergeant S.
        • Rahbar E.
        • Chilton F.H.
        Gamma-linolenic acid, dihommo-gamma linolenic, eicosanoids and inflammatory processes.
        Eur. J. Pharmacol. 2016; 785: 77-86https://doi.org/10.1016/j.ejphar.2016.04.020
        • 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. (Lond). 2011; 8: 1-15https://doi.org/10.1186/1743-7075-8-36
        • Vangaveti V.N.
        • Jansen H.
        • Kennedy R.L.
        • Malabu U.H.
        Hydroxyoctadecadienoic acids: oxidised derivatives of linoleic acid and their role in inflammation associated with metabolic syndrome and cancer.
        Eur. J. Pharmacol. 2016; 785: 70-76https://doi.org/10.1016/j.ejphar.2015.03.096
        • Shearer G.C.
        • Walker R.E.
        Omega-6 oxylipins – Synthesis in physiological PUFA mixtures and potential benefits.
        Prostagland. Leukot. Essent. Fatty Acids. 2018;
        • Pischon T.
        • Hankinson S.E.
        • Hotamisligil G.S.
        • Rifai N.
        • Willett W.C.
        • Rimm E.B.
        Habitual dietary intake of n-3 and n-6 fatty acids in relation to inflammatory markers among US men and women.
        Circulation. 2003; 108: 155-160https://doi.org/10.1161/01.CIR.0000079224.46084.C2
        • Ferrucci L.
        • Cherubini A.
        • Bandinelli S.
        • Bartali B.
        • Corsi A.
        • Lauretani F.
        • Martin A.
        • Andres-Lacueva C.
        • Senin U.
        • Guralnik J.M.
        Relationship of plasma polyunsaturated fatty acids to circulating inflammatory markers.
        J. Clin. Endocrinol. Metab. 2006; 91: 439-446https://doi.org/10.1210/jc.2005-1303
        • 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: 1029-1041https://doi.org/10.1016/j.jand.2012.03.029
        • Calder P.C.
        Marine omega-3 fatty acids and inflammatory processes: effects, mechanisms and clinical relevance.
        Biochim. Biophys. Acta Mol. Cell. Biol. Lipids. 2015; 1851: 469-484https://doi.org/10.1016/j.bbalip.2014.08.010
        • Calder P.C.
        Omega-3 fatty acids and inflammatory processes: from molecules to man.
        Biochem. Soc. Trans. 2017; 45: 1105-1115https://doi.org/10.1042/BST20160474
        • Goldberg R.J.
        • Katz J.
        A meta-analysis of the analgesic effects of omega-3 polyunsaturated fatty acid supplementation for inflammatory joint pain.
        Pain. 2007; 129: 210-223https://doi.org/10.1016/j.pain.2007.01.020
        • Abdulrazaq M.
        • Innes J.K.
        • Calder P.C.
        Effect of ω-3 polyunsaturated fatty acids on arthritic pain: a systematic review.
        Nutrition. 2017; 39–40: 57-66https://doi.org/10.1016/j.nut.2016.12.003
        • Senftleber N.K.
        • Nielsen S.M.
        • Andersen J.R.
        • Bliddal H.
        • Tarp S.
        • Lauritzen L.
        • Furst D.E.
        • Suarez-Almazor M.E.
        • Lyddiatt A.
        • Christensen R.
        Marine oil supplements for arthritis pain: a systematic review and meta-analysis of randomized trials.
        Nutrients. 2017; 9: 42https://doi.org/10.3390/nu9010042
        • Ramsden C.
        • Faurot K.R.
        • Zamora D.
        • Suchindran C.M.
        • Macintosh B.A.
        • Gaylord S.
        • Ringel A.
        • Hibbeln J.R.
        • Feldstein A.E.
        • Mori T.A.
        • Barden A.
        • Lynch C.
        • Coble R.
        • Mas E.
        • Palsson O.
        • Barrow D.A.
        • Mann J.D.
        Targeted alteration of dietary n-3 and n-6 fatty acids for the treatment of chronic headaches: a randomized trial.
        Pain. 2013; 154: 2441-2451https://doi.org/10.1016/j.pain.2013.07.028
        • Adam O.
        • Beringer C.
        • Kless T.
        • Lemmen C.
        • Adam A.
        • Wiseman M.
        • Adam P.
        • Klimmek R.
        • Forth W.
        Anti-inflammatory effects of a low arachidonic acid diet and fish oil in patients with rheumatoid arthritis.
        Rheumatol. Int. 2003; 23: 27-36https://doi.org/10.1007/s00296-002-0234-7
        • Wada M.
        • DeLong C.J.
        • Hong Y.H.
        • Rieke C.J.
        • Song I.
        • Sidhu R.S.
        • Yuan C.
        • Warnock M.
        • Schmaier A.H.
        • Yokoyama C.
        • Smyth E.M.
        • Wilson S.J.
        • FitzGerald G.A.
        • Garavito R.M.
        • De X.S.
        • Regan J.W.
        • Smith W.L.
        Enzymes and receptors of prostaglandin pathways with arachidonic acid-derived versus eicosapentaenoic acid-derived substrates and products.
        J. Biol. Chem. 2007; 282: 22254-22266https://doi.org/10.1074/jbc.M703169200
        • Chan J.K.
        • McDonald B.E.
        • Gerrard J.M.
        • Bruce V.M.
        • Weaver B.J.
        • Holub B.J.
        Effect of dietary α-linolenic acid and its ratio to linoleic acid on platelet and plasma fatty acids and thrombogenesis.
        Lipids. 1993; 28: 811-817https://doi.org/10.1007/BF02536235
        • Baker E.J.
        • Miles E.A.
        • Burdge G.C.
        • Yaqoob P.
        • Calder P.C.
        Metabolism and functional effects of plant-derived omega-3 fatty acids in humans.
        Prog. Lipid Res. 2016; 64: 30-56https://doi.org/10.1016/j.plipres.2016.07.002