Login Register Cart 0
Generic placeholder image

Current Cardiology Reviews

Editor-in-Chief

ISSN (Print): 1573-403X
ISSN (Online): 1875-6557

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Review Article

The Role of Triglycerides in Atherosclerosis: Recent Pathophysiologic Insights and Therapeutic Implications

Author(s): Yonatan Akivis*, Hussam Alkaissi, Samy I. McFarlane and Inna Bukharovich

Volume 20, Issue 2, 2024

Published on: 26 January, 2024

Article ID: e260124226400 Pages: 11

DOI: 10.2174/011573403X272750240109052319

Price: $65

Abstract

Triglycerides have long been recognized as a cardiovascular disease risk factor. However, their precise role in atherosclerosis and potential utility as a therapeutic target remains debated topics. This review aims to shed light on these aspects by exploring the complex relationship between triglycerides and atherosclerosis from pathophysiological and pharmacological perspectives.

Triglycerides, primarily carried by chylomicrons and very low-density lipoproteins, play an essential role in energy storage and utilization. Dysregulation of triglyceride homeostasis and triglyceride- rich lipoproteins metabolism often leads to hypertriglyceridemia and subsequently increases atherosclerosis risk. Triglyceride-rich lipoproteins remnants interact with arterial wall endothelial cells, get retained in the subendothelial space, and elicit inflammatory responses, thereby accelerating atherogenesis.

Despite the clear association between high triglyceride levels and increased cardiovascular disease risk, intervention trials targeting triglyceride reduction have produced mixed results. We discuss a range of triglyceride-lowering agents, from fibrates to omega-3 fatty acids, with a focus on their mechanism of action, efficacy, and major clinical trial outcomes. Notably, the role of newer agents, such as angiopoietin-like protein 3 and apolipoprotein C3 inhibitors, is also explored. We highlight the challenges and controversies, including the ongoing debate on the causal role of triglyceride in atherosclerosis and the discordant outcomes of recent clinical trials. The potential confounding effects of associated risk factors, such as elevated apolipoprotein B, insulin resistance, and metabolic syndrome, are considered.

In conclusion, this review underscores the importance of a nuanced approach to understanding the role of triglycerides in atherosclerosis and their potential as a therapeutic target. Further research is needed to unravel the complex interplay between triglycerides, triglyceride-rich lipoproteins, and associated factors in atherosclerosis pathogenesis and refine triglyceride-targeted therapeutic strategies.

Keywords: Triglycerides, atherosclerosis, cardiovascular disease, lipoprotein metabolism, hypertriglyceridemia, metabolic syndrome, insulin resistance.

Graphical Abstract

[1]
Nelson DL, Cox MM. Lehninger Principles of Biochemistry. (7th ed.), New York: W.H. Freeman and Company 2017.
[2]
Grundy SM. Hypertriglyceridemia, atherogenic dyslipidemia, and the metabolic syndrome. Am J Cardiol 1998; 81(4): 18B-25B.
[http://dx.doi.org/10.1016/S0002-9149(98)00033-2] [PMID: 9526809]
[3]
Miller M, Stone NJ, Ballantyne C, et al. Triglycerides and cardiovascular disease: A scientific statement from the american heart association. Circulation 2011; 123(20): 2292-333.
[http://dx.doi.org/10.1161/CIR.0b013e3182160726] [PMID: 21502576]
[4]
Ross R. Atherosclerosis--An inflammatory disease. N Engl J Med 1999; 340(2): 115-26.
[http://dx.doi.org/10.1056/NEJM199901143400207] [PMID: 9887164]
[5]
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.
[http://dx.doi.org/10.1093/eurheartj/ehx144] [PMID: 28444290]
[6]
Nordestgaard BG. Triglyceride-rich lipoproteins and atherosclerotic cardiovascular disease. Circ Res 2016; 118(4): 547-63.
[http://dx.doi.org/10.1161/CIRCRESAHA.115.306249] [PMID: 26892957]
[7]
Baigent C, Blackwell L, Emberson J, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: A meta-analysis of data from 170 000 participants in 26 randomised trials. Lancet 2010; 376(9753): 1670-81.
[http://dx.doi.org/10.1016/S0140-6736(10)61350-5] [PMID: 21067804]
[8]
Chapman MJ, Ginsberg HN, Amarenco P, et al. Triglyceride-rich lipoproteins and high-density lipoprotein cholesterol in patients at high risk of cardiovascular disease: Evidence and guidance for management. Eur Heart J 2011; 32(11): 1345-61.
[http://dx.doi.org/10.1093/eurheartj/ehr112] [PMID: 21531743]
[9]
Ginsberg HN, Packard CJ, Chapman MJ, et al. Triglyceride-rich lipoproteins and their remnants: Metabolic insights, role in atherosclerotic cardiovascular disease, and emerging therapeutic strategies-a consensus statement from the European Atherosclerosis Society. Eur Heart J 2021; 42(47): 4791-806.
[http://dx.doi.org/10.1093/eurheartj/ehab551] [PMID: 34472586]
[10]
Di Angelantonio E, Sarwar N, Perry P, et al. Major lipids, apolipoproteins, and risk of vascular disease. JAMA 2009; 302(18): 1993-2000.
[http://dx.doi.org/10.1001/jama.2009.1619] [PMID: 19903920]
[11]
Bhatt DL, Steg PG, Miller M, et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med 2019; 380(1): 11-22.
[http://dx.doi.org/10.1056/NEJMoa1812792] [PMID: 30415628]
[12]
Xiao C, Stahel P, Lewis GF. Regulation of chylomicron secretion: Focus on post-assembly mechanisms. Cell Mol Gastroenterol Hepatol 2019; 7(3): 487-501.
[http://dx.doi.org/10.1016/j.jcmgh.2018.10.015] [PMID: 30819663]
[13]
Hussain MM, Fatma S, Pan X, Iqbal J. Intestinal lipoprotein assembly. Curr Opin Lipidol 2005; 16(3): 281-5.
[http://dx.doi.org/10.1097/01.mol.0000169347.53568.5a] [PMID: 15891388]
[14]
Levy E, Beaulieu JF, Spahis S. From congenital disorders of fat malabsorption to understanding intra-enterocyte mechanisms behind chylomicron assembly and secretion. Front Physiol 2021; 12: 629222.
[http://dx.doi.org/10.3389/fphys.2021.629222] [PMID: 33584351]
[15]
Olofsson SO, Borèn J, Apolipoprotein B. Apolipoprotein B: A clinically important apolipoprotein which assembles atherogenic lipoproteins and promotes the development of atherosclerosis. J Intern Med 2005; 258(5): 395-410.
[http://dx.doi.org/10.1111/j.1365-2796.2005.01556.x] [PMID: 16238675]
[16]
Barrows BR, Parks EJ. Contributions of different fatty acid sources to very low-density lipoprotein-triacylglycerol in the fasted and fed states. J Clin Endocrinol Metab 2006; 91(4): 1446-52.
[http://dx.doi.org/10.1210/jc.2005-1709] [PMID: 16449340]
[17]
Donnelly KL, Smith CI, Schwarzenberg SJ, Jessurun J, Boldt MD, Parks EJ. 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.
[http://dx.doi.org/10.1172/JCI23621] [PMID: 15864352]
[18]
Goldberg IJ. Lipoprotein lipase and lipolysis: Central roles in lipoprotein metabolism and atherogenesis. J Lipid Res 1996; 37(4): 693-707.
[http://dx.doi.org/10.1016/S0022-2275(20)37569-6] [PMID: 8732771]
[19]
Kersten S. Physiological regulation of lipoprotein lipase. Biochim Biophys Acta Mol Cell Biol Lipids 2014; 1841(7): 919-33.
[http://dx.doi.org/10.1016/j.bbalip.2014.03.013] [PMID: 24721265]
[20]
Taskinen MR, Nikkilä EA, Nousiainen R, Gordin A. Lipoprotein lipase activity in adipose tissue and skeletal muscle of human diabetics during insulin deprivation and restoration. Scand J Clin Lab Invest 1981; 41(3): 263-8.
[http://dx.doi.org/10.3109/00365518109092043] [PMID: 7031837]
[21]
Wolska A, Reimund M, Remaley AT. Apolipoprotein C-II: The re-emergence of a forgotten factor. Curr Opin Lipidol 2020; 31(3): 147-53.
[http://dx.doi.org/10.1097/MOL.0000000000000680] [PMID: 32332429]
[22]
Dai W, Zhang Z, Yao C, Zhao S. Emerging evidences for the opposite role of apolipoprotein C3 and apolipoprotein A5 in lipid metabolism and coronary artery disease. Lipids Health Dis 2019; 18(1): 220.
[http://dx.doi.org/10.1186/s12944-019-1166-5] [PMID: 31836003]
[23]
Mahley RW, Huang Y, Apolipoprotein E. Apolipoprotein e sets the stage: Response to injury triggers neuropathology. Neuron 2012; 76(5): 871-85.
[http://dx.doi.org/10.1016/j.neuron.2012.11.020] [PMID: 23217737]
[24]
Heeren J, Beisiegel U, Grewal T, Apolipoprotein E. Apolipoprotein E recycling: Implications for dyslipidemia and atherosclerosis. Arterioscler Thromb Vasc Biol 2006; 26(3): 442-8.
[http://dx.doi.org/10.1161/01.ATV.0000201282.64751.47] [PMID: 16373604]
[25]
Hussain MM, Strickland DK, Bakillah A. The mammalian low-density lipoprotein receptor family. Annu Rev Nutr 1999; 19(1): 141-72.
[http://dx.doi.org/10.1146/annurev.nutr.19.1.141] [PMID: 10448520]
[26]
Mahley RW, Innerarity TL, Rall SC Jr, Weisgraber KH. Plasma lipoproteins: Apolipoprotein structure and function. J Lipid Res 1984; 25(12): 1277-94.
[http://dx.doi.org/10.1016/S0022-2275(20)34443-6] [PMID: 6099394]
[27]
Cuchel M, Rader DJ. Macrophage reverse cholesterol transport: Key to the regression of atherosclerosis? Circulation 2006; 113(21): 2548-55.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.104.475715] [PMID: 16735689]
[28]
Althaher AR. An overview of Hormone-Sensitive Lipase (HSL). ScientificWorldJournal 2022; 2022: 1-9.
[http://dx.doi.org/10.1155/2022/1964684] [PMID: 36530555]
[29]
Samuel VT, Shulman GI. Nonalcoholic fatty liver disease as a nexus of metabolic and hepatic diseases. Cell Metab 2018; 27(1): 22-41.
[http://dx.doi.org/10.1016/j.cmet.2017.08.002] [PMID: 28867301]
[30]
Beigneux AP, Davies BSJ, Gin P, et al. Glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 plays a critical role in the lipolytic processing of chylomicrons. Cell Metab 2007; 5(4): 279-91.
[http://dx.doi.org/10.1016/j.cmet.2007.02.002] [PMID: 17403372]
[31]
Tarugi P, Averna M, Di Leo E, et al. Molecular diagnosis of hypobetalipoproteinemia: An ENID review. Atherosclerosis 2007; 195(2): e19-27.
[http://dx.doi.org/10.1016/j.atherosclerosis.2007.05.003] [PMID: 17570373]
[32]
Reimund M, Wolska A, Risti R, et al. Apolipoprotein C-II mimetic peptide is an efficient activator of lipoprotein lipase in human plasma as studied by a calorimetric approach. Biochem Biophys Res Commun 2019; 519(1): 67-72.
[http://dx.doi.org/10.1016/j.bbrc.2019.08.130] [PMID: 31477272]
[33]
Castelli WP, Garrison RJ, Wilson PW, Abbott RD, Kalousdian S, Kannel WB. Incidence of coronary heart disease and lipoprotein cholesterol levels. The framingham study. JAMA 1986; 256(20): 2835-8.
[http://dx.doi.org/10.1001/jama.1986.03380200073024] [PMID: 3773200]
[34]
Nordestgaard BG, Benn M, Schnohr P, Tybjærg-Hansen A. Nonfasting triglycerides and risk of myocardial infarction, ischemic heart disease, and death in men and women. JAMA 2007; 298(3): 299-308.
[http://dx.doi.org/10.1001/jama.298.3.299] [PMID: 17635890]
[35]
Sarwar N, Danesh J, Eiriksdottir G, et al. Triglycerides and the risk of coronary heart disease: 10,158 incident cases among 262,525 participants in 29 Western prospective studies. Circulation 2007; 115(4): 450-8.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.106.637793] [PMID: 17190864]
[36]
Weber C, Noels H. Atherosclerosis: Current pathogenesis and therapeutic options. Nat Med 2011; 17(11): 1410-22.
[http://dx.doi.org/10.1038/nm.2538] [PMID: 22064431]
[37]
Moore KJ, Tabas I. Macrophages in the pathogenesis of atherosclerosis. Cell 2011; 145(3): 341-55.
[http://dx.doi.org/10.1016/j.cell.2011.04.005] [PMID: 21529710]
[38]
Majack RA, Castle CK, Goodman LV, et al. Expression of apolipoprotein E by cultured vascular smooth muscle cells is controlled by growth state. J Cell Biol 1988; 107(3): 1207-13.
[http://dx.doi.org/10.1083/jcb.107.3.1207] [PMID: 2458361]
[39]
Doi H, Kugiyama K, Oka H, et al. Remnant lipoproteins induce proatherothrombogenic molecules in endothelial cells through a redox-sensitive mechanism. Circulation 2000; 102(6): 670-6.
[http://dx.doi.org/10.1161/01.CIR.102.6.670] [PMID: 10931808]
[40]
Doi H, Kugiyama K, Ohgushi M, et al. Remnants of chylomicron and very low density lipoprotein impair endothelium-dependent vasorelaxation. Atherosclerosis 1998; 137(2): 341-9.
[http://dx.doi.org/10.1016/S0021-9150(97)00291-8] [PMID: 9622277]
[41]
Tall AR. Plasma cholesteryl ester transfer protein. J Lipid Res 1993; 34(8): 1255-74.
[http://dx.doi.org/10.1016/S0022-2275(20)36957-1] [PMID: 8409761]
[42]
Barter PJ, Caulfield M, Eriksson M, et al. Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med 2007; 357(21): 2109-22.
[http://dx.doi.org/10.1056/NEJMoa0706628] [PMID: 17984165]
[43]
Packard C, Caslake M, Shepherd J. The role of small, dense low density lipoprotein (LDL): A new look. Int J Cardiol 2000; 74 (Suppl. 1): S17-22.
[http://dx.doi.org/10.1016/S0167-5273(99)00107-2] [PMID: 10856769]
[44]
Wu B, Yu Z, Tong T, et al. Evaluation of small dense low-density lipoprotein concentration for predicting the risk of acute coronary syndrome in Chinese population. J Clin Lab Anal 2020; 34(3): e23085.
[http://dx.doi.org/10.1002/jcla.23085] [PMID: 31696980]
[45]
Staels B, Dallongeville J, Auwerx J, Schoonjans K, Leitersdorf E, Fruchart JC. Mechanism of action of fibrates on lipid and lipoprotein metabolism. Circulation 1998; 98(19): 2088-93.
[http://dx.doi.org/10.1161/01.CIR.98.19.2088] [PMID: 9808609]
[46]
Keech A, Simes RJ, Barter P, et al. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): Randomised controlled trial. Lancet 2005; 366(9500): 1849-61.
[http://dx.doi.org/10.1016/S0140-6736(05)67667-2] [PMID: 16310551]
[47]
Rubins HB, Robins SJ, Collins D, et al. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. N Engl J Med 1999; 341(6): 410-8.
[http://dx.doi.org/10.1056/NEJM199908053410604] [PMID: 10438259]
[48]
Frick MH, Elo O, Haapa K, et al. Helsinki heart study: Primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia. Safety of treatment, changes in risk factors, and incidence of coronary heart disease. N Engl J Med 1987; 317(20): 1237-45.
[http://dx.doi.org/10.1056/NEJM198711123172001] [PMID: 3313041]
[49]
Ginsberg HN, Elam MB, Lovato LC, et al. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med 2010; 362(17): 1563-74.
[http://dx.doi.org/10.1056/NEJMoa1001282] [PMID: 20228404]
[50]
Kashyap ML. Mechanism of action of niacin. Am J Cardiol 2008; 101(8A): 20B-6B.
[PMID: 18375237]
[51]
Canner PL, Berge KG, Wenger NK, et al. Fifteen year mortality in Coronary Drug Project patients: Long-term benefit with niacin. J Am Coll Cardiol 1986; 8(6): 1245-55.
[http://dx.doi.org/10.1016/S0735-1097(86)80293-5] [PMID: 3782631]
[52]
Boden WE, Probstfield JL, Anderson T, et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med 2011; 365(24): 2255-67.
[http://dx.doi.org/10.1056/NEJMoa1107579] [PMID: 22085343]
[53]
HPS2-THRIVE Collaborative Group effects of extended-release niacin with laropiprant in high-risk patients. New Engl J Med 2014; 371(3): 203-12.
[54]
Calder PC. Omega-3 fatty acids and inflammatory processes: From molecules to man. Biochem Soc Trans 2017; 45(5): 1105-15.
[http://dx.doi.org/10.1042/BST20160474] [PMID: 28900017]
[55]
Yokoyama M, Origasa H, Matsuzaki M, et al. 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.
[http://dx.doi.org/10.1016/S0140-6736(07)60527-3] [PMID: 17398308]
[56]
Nicholls SJ, Lincoff AM, Garcia M, et al. Effect of high-dose omega-3 fatty acids vs. corn oil on major adverse cardiovascular events in patients at high cardiovascular risk. JAMA 2020; 324(22): 2268-80.
[http://dx.doi.org/10.1001/jama.2020.22258] [PMID: 33190147]
[57]
Gaudet D, Brisson D, Tremblay K, et al. Targeting APOC3 in the familial chylomicronemia syndrome. N Engl J Med 2014; 371(23): 2200-6.
[http://dx.doi.org/10.1056/NEJMoa1400284] [PMID: 25470695]
[58]
Santos RD, Brinton EA. APOC3 as a cardiovascular risk factor and modulation by the novel therapy volanesorsen. Curr Atheroscler Rep 2020; 22(3): 11.
[PMID: 32328843]
[59]
Borén J, Taskinen MR, Björnson E, Packard CJ. Metabolism of triglyceride-rich lipoproteins in health and dyslipidaemia. Nat Rev Cardiol 2022; 19(9): 577-92.
[http://dx.doi.org/10.1038/s41569-022-00676-y] [PMID: 35318466]
[60]
Witztum JL, Gaudet D, Freedman SD, et al. Volanesorsen and triglyceride levels in familial chylomicronemia syndrome. N Engl J Med 2019; 381(6): 531-42.
[http://dx.doi.org/10.1056/NEJMoa1715944] [PMID: 31390500]
[61]
Digenio A, Dunbar RL, Alexander VJ, et al. Antisense-mediated lowering of plasma apolipoprotein C-III by volanesorsen improves dyslipidemia and insulin sensitivity in type 2 diabetes. Diabetes Care 2016; 39(8): 1408-15.
[http://dx.doi.org/10.2337/dc16-0126] [PMID: 27271183]
[62]
Ishibashi S, Yamashita S, Arai H, Araki E, Yokote K, Suganami H. Effects of K-877, a Novel Selective PPARα Modulator (SPPARMα), in Dyslipidaemic Patients: A Randomized, Double Blind, Active- and Placebo-Controlled, Phase 2 Trial. Atherosclerosis 2018; 27(1): 118-26.
[63]
Fruchart JC. Selective peroxisome proliferator-activated receptorα modulators (SPPARMα): The next generation of peroxisome proliferator-activated receptor α-agonists. Cardiovasc Diabetol 2013; 12(1): 82.
[http://dx.doi.org/10.1186/1475-2840-12-82] [PMID: 23721199]
[64]
Das Pradhan A, Glynn RJ, Fruchart JC, et al. Triglyceride lowering with pemafibrate to reduce cardiovascular risk. N Engl J Med 2022; 387(21): 1923-34.
[http://dx.doi.org/10.1056/NEJMoa2210645] [PMID: 36342113]
[65]
Dewey FE, Gusarova V, Dunbar RL, et al. Genetic and pharmacologic inactivation of ANGPTL3 and cardiovascular disease. N Engl J Med 2017; 377(3): 211-21.
[http://dx.doi.org/10.1056/NEJMoa1612790] [PMID: 28538136]
[66]
Dijk W, Kersten S. Regulation of lipid metabolism by angiopoietin-like proteins. Curr Opin Lipidol 2016; 27(3): 249-56.
[http://dx.doi.org/10.1097/MOL.0000000000000290] [PMID: 27023631]
[67]
Raal FJ, Rosenson RS, Reeskamp LF, et al. Evinacumab for homozygous familial hypercholesterolemia. N Engl J Med 2020; 383(8): 711-20.
[http://dx.doi.org/10.1056/NEJMoa2004215] [PMID: 32813947]

Rights & Permissions Print Cite
Article Metrics
20
2
© 2024 Bentham Science Publishers | Privacy Policy