Abstract
Cardiovascular disease (CVD) is the world’s most recognized and notorious cause of death. It is known that increased triglyceride-rich lipoproteins (TRLs) and remnants of triglyceride-rich lipoproteins (RLP) are the major risk factor for CVD. Furthermore, hypertriglyceridemia commonly leads to a reduction in HDL and an increase in atherogenic small dense low-density lipoprotein (sdLDL or LDL-III) levels. Thus, the evidence shows that Ω-3 fatty acids (eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have a beneficial effect on CVD through reprogramming of TRL metabolism, reducing inflammatory mediators (cytokines and leukotrienes), and modulation of cell adhesion molecules. Therefore, the purpose of this review is to provide the molecular mechanism related to the beneficial effect of Ω-3 PUFA on the lowering of plasma TAG levels and other atherogenic lipoproteins. Taking this into account, this study also provides the TRL lowering and anti-inflammatory mechanism of Ω-3 PUFA metabolites such as RvE1 and RvD2 as a cardioprotective function.
Similar content being viewed by others
References
Kris-Etherton PM, Harris WS, Appel LJ (2002) Fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease. Circulation 106(21):2747–2757
Harris WS et al (2008) Omega-3 fatty acids and coronary heart disease risk: clinical and mechanistic perspectives. Atherosclerosis 197(1):12–24
Palmquist DL (2009) Omega-3 fatty acids in metabolism, health, and nutrition and for modified animal product foods. Prof Ani Sci 25(3):207–249
Harris WS (1997) n-3 fatty acids and serum lipoproteins: human studies. Am J Clin Nutr 65(5):1645S–1654S
Calvo MJ et al (2017) Omega-3 polyunsaturated fatty acids and cardiovascular health: a molecular view into structure and function. Vessel Plus 1(3):116–128
Reimers A, Ljung H (2019) The emerging role of omega-3 fatty acids as a therapeutic option in neuropsychiatric disorders. Therap Adv Psychopharmacol 9:2045125319858901
Shahidi F, Ambigaipalan P (2018) Omega-3 polyunsaturated fatty acids and their health benefits. Annu Rev Food Sci Technol 9:345–381
Calder PC (2017) Omega-3 fatty acids and inflammatory processes: from molecules to man. Biochem Soc Trans 45(5):1105–1115
Mohebi-Nejad A, Bikdeli B (2014) Omega-3 supplements and cardiovascular diseases. Tanaffos 13(1):6
Sampath H, Ntambi JM (2005) Polyunsaturated fatty acid regulation of genes of lipid metabolism. Annu Rev Nutr 25:317–340
Bradberry JC, Hilleman DE (2013) Overview of omega-3 fatty acid therapies. Pharm Ther 38(11):681
Kris-Etherton PM et al (2008) The role of tree nuts and peanuts in the prevention of coronary heart disease: multiple potential mechanisms. J Nutr 138(9):1746S–1751S
Xu Y et al (2014) Is the jury still out on the benefits of fish, seal and flax oils in cardiovascular disease. Ann Nutr Disord Ther 1:40
Calder PC (2015) Marine omega-3 fatty acids and inflammatory processes: effects, mechanisms and clinical relevance. Biochimica et Biophysica Acta (BBA) Mol Cell Biol Lipids 1851(4):469–484
Holub DJ, Holub BJ (2004) Omega-3 fatty acids from fish oils and cardiovascular disease. Mol Cell Biochem 263(1):217–225
Shaikh NA, Tappia PS (2015) Why are there inconsistencies in the outcomes of some omega-3 fatty acid trials for the management of cardiovascular disease? Clin Lipidol 10(1):27–32
Gammone MA et al (2019) Omega-3 polyunsaturated fatty acids: benefits and endpoints in sport. Nutrients 11(1):46
Jacobson TA (2008) Role of n− 3 fatty acids in the treatment of hypertriglyceridemia and cardiovascular disease. Am J Clin Nutr 87(6):1981S–1990S
Skulas-Ray AC et al (2019) Omega-3 fatty acids for the management of hypertriglyceridemia: a science advisory from the American Heart Association. Circulation 140(12):e673–e691
National Cholesterol Education Program (US). Expert Panel on Detection, & Treatment of High Blood Cholesterol in Adults (2002) Third report of the National Cholesterol Education Program (NCEP) Expert Panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III) (No. 2). National Cholesterol Education Program, National Heart, Lung, and Blood Institute, National Institutes of Health
Blair HA, Dhillon S (2014) Omega-3 carboxylic acids (epanova®): a review of its use in patients with severe hypertriglyceridemia. Am J Cardiovasc Drugs 14(5):393–400
Yokoyama M et al (2007) Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis. Lancet 369(9567):1090–1098
Mason RP (2019) New insights into mechanisms of action for omega-3 fatty acids in atherothrombotic cardiovascular disease. Curr Atheroscler Rep 21(1):2
Adkins Y, Kelley DS (2010) Mechanisms underlying the cardioprotective effects of omega-3 polyunsaturated fatty acids. J Nutr Biochem 21(9):781–792
Langsted A, Madsen CM, Nordestgaard BG (2020) Contribution of remnant cholesterol to cardiovascular risk. J Intern Med 288(1):116–127
Bhatt DL et al (2017) Rationale and design of REDUCE-IT: reduction of cardiovascular events with icosapent ethyl–intervention trial. Clin Cardiol 40(3):138–148
Kim ES, McCormack PL (2014) Icosapent ethyl: a review of its use in severe hypertriglyceridemia. Am J Cardiovasc Drugs 14(6):471–478
Sacks FM et al (2000) VLDL, apolipoproteins B, CIII, and E, and risk of recurrent coronary events in the Cholesterol and Recurrent Events (CARE) trial. Circulation 102(16):1886–1892
Kang S, Davis RA (2000) Cholesterol and hepatic lipoprotein assembly and secretion. Biochimica et Biophysica Acta (BBA) Mol Cell Biol Lipids 1529(1-3):223–230
Sacks FM (2015) The crucial roles of apolipoproteins E and C-III in apoB lipoprotein metabolism in normolipidemia and hypertriglyceridemia. Curr Opin Lipidol 26(1):56
Wolska A et al (2017) Apolipoprotein C-II: new findings related to genetics, biochemistry, and role in triglyceride metabolism. Atherosclerosis 267:49–60
Arca M et al (2018) Hypertriglyceridemia and omega-3 fatty acids: their often overlooked role in cardiovascular disease prevention. Nutr Metab Cardiovasc Dis 28(3):197–205
Bays HE et al (2008) Prescription omega-3 fatty acids and their lipid effects: physiologic mechanisms of action and clinical implications. Expert Rev Cardiovasc Ther 6(3):391–409
Alves-Bezerra M, Cohen DE (2011) Triglyceride metabolism in the liver. Compr Physiol 8(1):1–22
Feingold KR, Grunfeld C (2018) Introduction to lipids and lipoproteins. In endotext [internet]. MDText. com, Inc
Dittrich J et al (2019) Plasma levels of apolipoproteins C-III, A-IV, and E are independently associated with stable atherosclerotic cardiovascular disease. Atherosclerosis 281:17–24
Rupp H (2009) Omacor®(prescription omega-3-acid ethyl esters 90): from severe rhythm disorders to hypertriglyceridemia. Adv Ther 26(7):675
Nordestgaard BG, Varbo A (2014) Triglycerides and cardiovascular disease. Lancet 384(9943):626–635
Bhatnagar D, Hussain F (2007) Omega-3 fatty acid ethyl esters (Omacor®) for the treatment of hypertriglyceridemia. Futur Lipidol 2(3):263–270
Thériault S et al (2016) Frameshift mutation in the APOA5 gene causing hypertriglyceridemia in a Pakistani family: management and considerations for cardiovascular risk. J Clin Lipidol 10(5):1272–1277
Pejic RN, Lee DT (2006) Hypertriglyceridemia. J Am Board Fam Med 19(3):310–316
Packard CJ, Boren J, Taskinen MR (2020) Causes and consequences of hypertriglyceridemia. Front Endocrinol 11:252
Parhofer KG, Laufs U (2019) The diagnosis and treatment of hypertriglyceridemia. Dtsch Arztebl Int 116(49):825
Ruhaak LR, van der Laarse A, Cobbaert CM (2019) Apolipoprotein profiling as a personalized approach to the diagnosis and treatment of dyslipidaemia. Ann Clin Biochem 56(3):338
Packard CJ, Saito Y (2004) Non− HDL cholesterol as a measure of atherosclerotic risk. J Atheroscler Thromb 11(1):6–14
Paredes S et al (2019) Novel and traditional lipid profiles in Metabolic Syndrome reveal a high atherogenicity. Sci Rep 9(1):1–7
Carr SS et al (2019) Non-HDL-cholesterol and apolipoprotein B compared with LDL-cholesterol in atherosclerotic cardiovascular disease risk assessment. Pathology 51(2):148–154
Sniderman AD (2005) Apolipoprotein B versus non–high-density lipoprotein cholesterol: and the winner is. Circulation 112(22):3366–3367
Pischon T et al (2005) Non–high-density lipoprotein cholesterol and apolipoprotein B in the prediction of coronary heart disease in men. Circulation 112(22):3375–3383
Miller M et al (2008) Impact of triglyceride levels beyond low-density lipoprotein cholesterol after acute coronary syndrome in the PROVE IT-TIMI 22 trial. J Am Coll Cardiol 51(7):724–730
Miller M, Ginsberg HN, Schaefer EJ (2008) Relative atherogenicity and predictive value of non–high-density lipoprotein cholesterol for coronary heart disease. Am J Cardiol 101(7):1003–1008
Robinson JG et al (2018) Eradicating the burden of atherosclerotic cardiovascular disease by lowering apolipoprotein B lipoproteins earlier in life. J Am Heart Assoc 7(20):e009778
Durrington PN (2002) Can measurement of apolipoprotein B replace the lipid profile in the follow-up of patients with lipoprotein disorders? Clin Chem 48(3):401–402
Campos H et al (2001) Low-density lipoprotein size, pravastatin treatment, and coronary events. Jama 286(12):1468–1474
Dai W et al (2019) Emerging evidences for the opposite role of apolipoprotein C3 and apolipoprotein A5 in lipid metabolism and coronary artery disease. Lipids Health Dis 18(1):220
Ramms B, Gordts PL (2018) Apolipoprotein C-III in triglyceride-rich lipoprotein metabolism. Curr Opin Lipidol 29(3):171–179
Kawakami A et al (2006) Apolipoprotein CIII induces expression of vascular cell adhesion molecule-1 (VCAM-1) in vascular endothelial cells and increases adhesion of monocytic cells. Circulation 114(7):681–687
Garg R, Rustagi T (2018) Management of hypertriglyceridemia induced acute pancreatitis. BioMed Res Int 2018:12
Shemesh E, Zafrir B (2019) Hypertriglyceridemia-related pancreatitis in patients with type 2 diabetes: links and risks. Diabetes Metab Syndr Obes Targets Ther 12:2041
Chan DC et al (2003) Randomized controlled trial of the effect of n–3 fatty acid supplementation on the metabolism of apolipoprotein B-100 and chylomicron remnants in men with visceral obesity. Am J Clin Nutr 77(2):300–307
Oscarsson J, Hurt-Camejo E (2017) Omega-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid and their mechanisms of action on apolipoprotein B-containing lipoproteins in humans: a review. Lipids Health Dis 16(1):149
Tanaka N et al (2010) Eicosapentaenoic acid improves hepatic steatosis independent of PPARα activation through inhibition of SREBP-1 maturation in mice. Biochem Pharmacol 80(10):1601–1612
Kim CW et al (2017) Acetyl CoA carboxylase inhibition reduces hepatic steatosis but elevates plasma triglycerides in mice and humans: a bedside to bench investigation. Cell Metab 26(2):394–406
Moon YA, Hammer RE, Horton JD (2009) Deletion of ELOVL5 leads to fatty liver through activation of SREBP-1c in mice. J Lipid Res 50(3):412–423
Ye J, DeBose-Boyd RA (2011) Regulation of cholesterol and fatty acid synthesis. Cold Spring Harb Perspect Biol 3(7):a004754
Watt MJ et al (2019) The liver as an endocrine organ—linking NAFLD and insulin resistance. Endocr Rev 40(5):1367–1393
Khwairakpam AD et al (2020) The vital role of ATP citrate lyase in chronic diseases. J Mol Med 98(1):71–95
Hunkeler M et al (2018) Structural basis for regulation of human acetyl-CoA carboxylase. Nature 558(7710):470–474
Davidson MH (2006) Mechanisms for the hypotriglyceridemic effect of marine omega-3 fatty acids. Am J Cardiol 98(4):27–33
McKenney JM, Sica D (2007) Prescription omega-3 fatty acids for the treatment of hypertriglyceridemia. Am J Health Syst Pharm 64(6):595–605
Jump J, D. B. (2002) The biochemistry of n-3 polyunsaturated fatty acids. J Biol Chem 277(11):8755–8758
Yoshikawa T et al (2002) 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 277(3):1705–1711
Xu X et al (2013) Transcriptional control of hepatic lipid metabolism by SREBP and ChREBP. Semin Liver Dis 33(4):301. NIH Public Access
Harris WS, Bulchandani D (2006) Why do omega-3 fatty acids lower serum triglycerides? Curr Opin Lipidol 17(4):387–393
Li D et al (2017) Identification of a novel human long non-coding RNA that regulates hepatic lipid metabolism by inhibiting SREBP-1c. Int J Biol Sci 13(3):349
Horton JD, Goldstein JL, Brown MS (2002) SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J Clin Invest 109(9):1125–1131
Kim HJ, Takahashi M, Ezaki O (1999) Fish oil feeding decreases mature sterol regulatory element-binding protein 1 (SREBP-1) by down-regulation of SREBP-1c mRNA in mouse liver a possible mechanism for down-regulation of lipogenic enzyme mRNAs. J Biol Chem 274(36):25892–25898
Rong S et al (2017) Expression of SREBP-1c requires SREBP-2-mediated generation of a sterol ligand for LXR in livers of mice. Elife 6:e25015
Tajima-Shirasaki N et al (2017) 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 292(26):10791–10800
Sagar NM et al (2016) Mechanisms of triglyceride metabolism in patients with bile acid diarrhea. World J Gastroenterol 22(30):6757
Neschen S et al (2002) Contrasting effects of fish oil and safflower oil on hepatic peroxisomal and tissue lipid content. Am J Physiol Endocrinol Metab 282(2):E395–E401
Chambrier C et al (2002) Eicosapentaenoic acid induces mRNA expression of peroxisome proliferator-activated receptor γ. Obes Res 10(6):518–525
Zhao A et al (2004) Polyunsaturated fatty acids are FXR ligands and differentially regulate expression of FXR targets. DNA Cell Biol 23(8):519–526
Sahebkar A et al (2018) Effect of omega-3 supplements on plasma apolipoprotein C-III concentrations: a systematic review and meta-analysis of randomized controlled trials. Ann Med 50(7):565–575
Siscovick DS et al (2017) Omega-3 polyunsaturated fatty acid (fish oil) supplementation and the prevention of clinical cardiovascular disease: a science advisory from the American Heart Association. Circulation 135(15):e867–e884
Endo J, Arita M (2016) Cardioprotective mechanism of omega-3 polyunsaturated fatty acids. J Cardiol 67(1):22–27
Darwesh AM et al (2019) Insights into the cardioprotective properties of n-3 PUFAs against ischemic heart disease via modulation of the innate immune system. Chem Biol Interact 308:20–44
Fredman G (2019) Can inflammation-resolution provide clues to treat patients according to their plaque phenotype? Front Pharmacol 10:205
Giacobbe J et al (2020) The anti-inflammatory role of omega-3 polyunsaturated fatty acids metabolites in pre-clinical models of psychiatric, neurodegenerative and neurological disorders. Front Psych 11:122
Wang F et al (2020) Specialized pro-resolving mediators: it’s anti-oxidant stress role in multiple disease models. Mol Immunol 126:40–45
Li Q et al (2020) Maresins: anti-inflammatory pro-resolving mediators with therapeutic potential. Eur Rev Med Pharmacol Sci 24(13):7442–7453
Mills SC, Windsor AC, Knight SC (2005) The potential interactions between polyunsaturated fatty acids and colonic inflammatory processes. Clin Exp Immunol 142(2):216–228
Simopoulos AP (2002) Omega-3 fatty acids in inflammation and autoimmune diseases. J Am Coll Nutr 21(6):495–505
Massaro M et al (2008) Omega–3 fatty acids, inflammation and angiogenesis: nutrigenomic effects as an explanation for anti-atherogenic and anti-inflammatory effects of fish and fish oils. Lifestyle Genomics 1(1-2):4–23
Viola JR et al (2016) Resolving lipid mediators maresin 1 and resolvin D2 prevent atheroprogression in mice. Circ Res 119(9):1030–1038
Thorp EB (2016) Proresolving lipid mediators restore balance to the vulnerable plaque. Am Heart Assoc 119:972–974
Fan YY et al (2003) Chemopreventive n-3 fatty acids activate RXRα in colonocytes. Carcinogenesis 24(9):1541–1548
Lalia AZ et al (2017) Influence of omega-3 fatty acids on skeletal muscle protein metabolism and mitochondrial bioenergetics in older adults. Aging (Albany NY) 9(4):1096
Calder PC (2010) Omega-3 fatty acids and inflammatory processes. Nutrients 2(3):355–374
Acknowledgements
I would like to forward my gratitude to the authors of the article, where I generate this review report.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Author information
Authors and Affiliations
Contributions
TS: Conceived the design, searching the literature, drafting, editing and wrote the whole manuscript.
Corresponding author
Ethics declarations
Conflict of interest
The author declares that there is no competing interest.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Shibabaw, T. Omega-3 polyunsaturated fatty acids: anti-inflammatory and anti-hypertriglyceridemia mechanisms in cardiovascular disease. Mol Cell Biochem 476, 993–1003 (2021). https://doi.org/10.1007/s11010-020-03965-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11010-020-03965-7