Apolipoprotein C-III: A potent modulator of hypertriglyceridemia and cardiovascular disease

Current Opinion in Endocrinology, Diabetes and Obesity

Volumn 22, Issue 2, 2015, Pages 119-125

  Kohan, Alison B ^a  

^a UNIVERSITY OF CONNECTICUT   (United States)

Author keywords

apolipoprotein C III; cardiovascular disease; diabetes; intestinal lipid transport; obesity; vascular inflammation

Indexed keywords

APOLIPOPROTEIN C3; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE INHIBITOR; TRIACYLGLYCEROL; ANTILIPEMIC AGENT; AUTACOID; BIOLOGICAL MARKER;

APOPTOSIS; ATHEROGENESIS; CARDIOVASCULAR DISEASE; CARDIOVASCULAR RISK; GENE MUTATION; GENETIC LINKAGE; HUMAN; HYPERTRIGLYCERIDEMIA; NONHUMAN; PHASE 2 CLINICAL TRIAL (TOPIC); PROTEIN EXPRESSION; REVIEW; RISK REDUCTION; TRIACYLGLYCEROL BLOOD LEVEL; ANIMAL; BLOOD; CARDIOVASCULAR DISEASES; RISK FACTOR; SIGNAL TRANSDUCTION;

ANIMALS; APOLIPOPROTEIN C-III; BIOMARKERS; CARDIOVASCULAR DISEASES; HUMANS; HYPERTRIGLYCERIDEMIA; HYPOLIPIDEMIC AGENTS; INFLAMMATION MEDIATORS; RISK FACTORS; SIGNAL TRANSDUCTION; TRIGLYCERIDES;

EID: 84926303879     PISSN: 1752296X     EISSN: 17522978     Source Type: Journal    
DOI: 10.1097/MED.0000000000000136     Document Type: Review

References (81)

1. Hobbs HH, Brown MS, Goldstein JL. Molecular genetics of the LDL receptor gene in familial hypercholesterolemia. Hum Mutat 1992; 1:445-466.
2. The Lipid Research Clinics Coronary Primary Prevention Trial results. I. Reduction in incidence of coronary heart disease. JAMA 1984; 251:351-364.
3. Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994; 344:1383-1389.
4. Gupta A, Smith DA. The 2013 American College of Cardiology/American Heart Association guidelines on treating blood cholesterol and assessing cardiovascular risk: a busy practitioners guide. Endocrinol Metab Clin North Am 2014; 43:869-892.
5. Superko HR, King S. Lipid management to reduce cardiovascular risk: a new strategy is required. Circulation 2008; 117:560-568.
6. Reiner Z. Managing the residual cardiovascular disease risk associated with HDL-cholesterol and triglycerides in statin-treated patients: a clinical update. Nutr Metab Cardiovasc Dis 2013; 23:799-807.
7. Di Angelantonio E, Sarwar N, Perry P, et al. Major lipids, apolipoproteins, and risk of vascular disease. JAMA 2009; 302:1993-2000.
8. Landray MJ, Haynes R, Hopewell JC, et al. Effects of extended-release niacin with laropiprant in high-risk patients. N Engl J Med 2014; 371:203-212.
9. HPS2-THRIVE Collaborative Group. HPS2-THRIVE randomized placebocontrolled trial in 25, 673 high-risk patients of ER niacin/laropiprant: trial design, prespecified muscle and liver outcomes, and reasons for stopping study treatment. Eur Heart J 2013; 34:1279-1291.
10. 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; 365:2255-2267.
11. Schwartz GG, Olsson AG, Abt M, et al. Effects of dalcetrapib in patients with a recent acute coronary syndrome. N Engl J Med 2012; 367:2089-2099.
12. Barter PJ, Caulfield M, Eriksson M, et al. Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med 2007; 357:2109-2122.
13. Voight BF, Peloso GM, Orho-Melander M, et al. Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study. Lancet 2012; 380:572-580.
14. Haase CL, Tybjrg-Hansen A, Qayyum AA, et al. LCAT, HDL cholesterol and ischemic cardiovascular disease: a Mendelian randomization study of HDL cholesterol in 54, 500 individuals. J Clin Endocrinol Metab 2012; 97:E248-E256.
15. Zilversmit DB. Atherogenesis: a postprandial phenomenon. Circulation 1979; 60:473-485.
16. Langsted A, Freiberg JJ, Tybjaerg-Hansen A, et al. Nonfasting cholesterol and triglycerides and association with risk of myocardial infarction and total mortality: the Copenhagen City Heart Study with 31 years of follow-up. J Intern Med 2011; 270:65-75.
17. Nordestgaard BG, Benn M, Schnohr P, Tybjaerg-Hansen A. Nonfasting triglycerides and risk of myocardial infarction, ischemic heart disease, and death in men and women. JAMA 2007; 298:299-308.
18. Otvos JD, Collins D, Freedman DS, et al. Low-density lipoprotein and highdensity lipoprotein particle subclasses predict coronary events and are favorably changed by gemfibrozil therapy in the Veterans Affairs High-Density Lipoprotein Intervention Trial. Circulation 2006; 113:1556-1563.
19. Berneis KK, Krauss RM. Metabolic origins and clinical significance of LDL heterogeneity. J Lipid Res 2002; 43:1363-1379.
20. Tabas I, Williams KJ, Boren J. Subendothelial lipoprotein retention as the initiating process in atherosclerosis: update and therapeutic implications. Circulation 2007; 116:1832-1844.
21. Zhang W-Y, Schwartz E, Wang Y, et al. Elevated concentrations of nonesterified fatty acids increase monocyte expression of CD11b and adhesion to endothelial cells. Arterioscler Thromb Vasc Biol 2006; 26:514-519.
22. Wang L, Gill R, Pedersen TL, et al. Triglyceride-rich lipoprotein lipolysis releases neutral and oxidized FFAs that induce endothelial cell inflammation. J Lipid Res 2009; 50:204-213.
23. Wang J, Xian X, Huang W, et al. Expression of LPL in endothelial-intact artery results in lipid deposition and vascular cell adhesion molecule-1 upregulation in both LPL and ApoE-deficient mice. Arterioscler Thromb Vasc Biol 2007; 27:197-203.
24. Miller M, Stone NJ, Ballantyne C, et al. Triglycerides and cardiovascular disease: a scientific statement from the American Heart Association. Circulation 2011; 123:2292-2333.
25. Ghandehari H, Le V, Kamal-Bahl S, et al. Abdominal obesity and the spectrum of global cardiometabolic risks in US adults. Int J Obes (Lond) 2009; 33:239-248.
26. Haddad IA, Ordovas JM, Fitzpatrick T, Karathanasis SK. Linkage, evolution, and expression of the rat apolipoprotein A-I, C-III, and A-IV genes. J Biol Chem 1986; 261:13268-13277.
27. Dallinga-Thie GM, Bu XD, van Linde-Sibenius Trip M, et al. Apolipoprotein A-I/C-III/A-IV gene cluster in familial combined hyperlipidemia: effects on LDL-cholesterol and apolipoproteins B and C-III. J Lipid Res 1996; 37:136-147.
28. Mar R, Pajukanta P, Allayee H, et al. Association of the APOLIPOPROTEIN A1/C3/A4/A5 gene cluster with triglyceride levels and LDL particle size in familial combined hyperlipidemia. Circ Res 2004; 94:993-999.
29. Lai C-Q, Parnell LD, Ordovas JM. The APOA1/C3/A4/A5 gene cluster, lipid metabolism and cardiovascular disease risk. Curr Opin Lipidol 2005; 16:153-166.
30. Qi L, Liu S, Rifai N, et al. Associations of the apolipoprotein A1/C3/A4/A5 gene cluster with triglyceride and HDL cholesterol levels in women with type 2 diabetes. Atherosclerosis 2007; 192:204-210.
31. Cohn JSJ, Tremblay M, Batal R, et al. Increased apoC-III production is a characteristic feature of patients with hypertriglyceridemia. Atherosclerosis 2004; 177:137-145.
32. Marcais C, Bernard S, Merlin M, et al. Severe hypertriglyceridaemia in Type II diabetes: involvement of apoC-III Sst-I polymorphism, LPL mutations and apo E3 deficiency. Diabetologia 2000; 43:1346-1352.
33. Onat A, Hergenc G, Ayhan E, et al. Serum apolipoprotein C-III in high-density lipoprotein: a key diabetogenic risk factor in Turks. Diabet Med 2009; 26:981-988.
34. Ooi EMM, Barrett PHR, Chan DC, Watts GF. Apolipoprotein C-III: understanding an emerging cardiovascular risk factor. Clin Sci (Lond) 2008; 114:611-624.
35. Sacks FM, Alaupovic P, Moye La, et al. VLDL, Apolipoproteins B, CIII, and E, and risk of recurrent coronary events in the Cholesterol and Recurrent Events (CARE) trial. Circulation 2000; 102:1886-1892.
36. Mahley RW, Innerarity TL, Rall SC, Weisgraber KH. Plasma lipoproteins: apolipoprotein structure and function. J Lipid Res 1984; 25:1277-1294.
37. Sehayek E, Eisenberg S. Mechanisms of inhibition by apolipoprotein C of apolipoprotein E-dependent cellular metabolism of human triglyceride-rich lipoproteins through the low density lipoprotein receptor pathway. J Biol Chem 1991; 266:18259-18267.
38. Windler E, Havel R. Inhibitory effects of C apolipoproteins from rats and humans on the uptake of triglyceride-rich lipoproteins and their remnants by the perfused rat liver. J Lipid Res 1985; 26:556-565.
39. Wang CS, McConathy WJ, Kloer HU, Alaupovic P. Modulation of lipoprotein lipase activity by apolipoproteins. Effect of apolipoprotein C-III. J Clin Invest 1985; 75:384-390.
40. Kinnunen PK, Ehnolm C. Effect of serum and C-apoproteins from very low density lipoproteins on human postheparin plasma hepatic lipase. FEBS Lett 1976; 65:354-357.
41. Sundaram M, Zhong S, Bou KhalilM, et al. Expression of apolipoprotein C-III in McA-RH7777 cells enhances VLDL assembly and secretion under lipid-rich conditions. J Lipid Res 2010; 51:150-161.
42. Wang F, Kohan AB, Dong HH, et al. Overexpression of apolipoprotein C-III decreases secretion of dietary triglyceride into lymph. Physiol Rep 2014; 2:e00247.
43. Pollin T, Damcott C, Shen H, et al. A null mutation in human APOC3 confers a favorable plasma lipid profile and apparent cardioprotection. Science 2008; 322:1702-1705.
44. Crawford DC, Dumitrescu L, Goodloe R, et al. Rare variant APOC3 R19X is associated with cardio-protective profiles in a diverse population-based survey as part of the Epidemiologic Architecture for Genes Linked to Environment (EAGLE) Study. Circ Cardiovasc Genet 2014; 7:848-853.
45. Atzmon G, Rincon M, Schechter CB, et al. Lipoprotein genotype and conserved pathway for exceptional longevity in humans. PLoS Biol 2006; 4:e113.
46. Blankenhorn DH, Alaupovic P, Wickham E, et al. Prediction of angiographic change in native human coronary arteries and aortocoronary bypass grafts. Lipid and nonlipid factors. Circulation 1990; 81:470-476.
47. Crosby J, Peloso GM, Auer PL, et al. Loss-of-function mutations in APOC3, triglycerides, and coronary disease. N Engl J Med 2014; 371:22-31.
48. Jrgensen AB, Frikke-Schmidt R, Nordestgaard BG, Tybjrg-Hansen A. Loss-of-function mutations in APOC3 and risk of ischemic vascular disease. N Engl J Med 2014; 371:32-41.
49. Nordestgaard BG, Varbo A. Triglycerides and cardiovascular disease. Lancet 2014; 384:626-635.
50. Goldberg IJ, Eckel RH, McPherson R. Triglycerides and heart disease: still a hypothesis? Arterioscler Thromb Vasc Biol 2011; 31:1716-1725.
51. Jackson RL, Tajima S, Yamamura T, et al. Comparison of apolipoprotein C-IIdeficient triacylglycerol-rich lipoproteins and trioleoylglycerol/phosphatidylcholine- stabilized particles as substrates for lipoprotein lipase. Biochim Biophys Acta 1986; 875:211-219.
52. Larsson M, VorrsjöE, Talmud P, et al. Apolipoproteins C-I and C-III inhibit lipoprotein lipase activity by displacement of the enzyme from lipid droplets. J Biol Chem 2013; 288:33997-34008.
53. Zheng C, Khoo C, Furtado J, Sacks FM. Apolipoprotein C-III and the metabolic basis for hypertriglyceridemia and the dense low-density lipoprotein phenotype. Circulation 2010; 121:1722-1734.
54. Sundaram M, Zhong S, Bou Khalil M, et al. Functional analysis of the missense APOC3 mutation Ala23Thr associated with human hypotriglyceridemia. J Lipid Res 2010; 51:1524-1534.
55. Cohn JS, Patterson BW, Uffelman KD, et al. Rate of production of plasma and very-low-density lipoprotein (VLDL) apolipoprotein C-III is strongly related to the concentration and level of production of VLDL triglyceride in male subjects with different body weights and levels of insulin sensitivity. J Clin Endocrinol Metab 2004; 89:3949-3955.
56. Jensen MK, Rimm EB, Furtado JD, Sacks FM. Apolipoprotein C-III as a potential modulator of the association between HDL-cholesterol and incident coronary heart disease. J Am Heart Assoc 2012. [Epub ahead of print]. doi:10.1161/JAHA.111.000232.
57. Riwanto M, Rohrer L, Roschitzki B, et al. Altered activation of endothelial anti and proapoptotic pathways by high-density lipoprotein from patients with coronary artery disease: role of high-density lipoprotein-proteome remodeling. Circulation 2013; 127:891-904.
58. Lee S-J, Campos H, Moye La, Sacks FM. LDL containing apolipoprotein CIII is an independent risk factor for coronary events in diabetic patients. Arterioscler Thromb Vasc Biol 2003; 23:853-858.
59. Mendivil CO, Rimm EB, Furtado J, et al. Low-density lipoproteins containing apolipoprotein C-III and the risk of coronary heart disease. Circulation 2011; 124:2065-2072.
60. Talayero B, Wang L, Furtado J, et al. Obesity favors apolipoprotein E- and C-III-containing high density lipoprotein subfractions associated with risk of heart disease. J Lipid Res 2014; 55:2167-2177.
61. Moore KJ, Tabas I. Macrophages in the pathogenesis of atherosclerosis. Cell 2011; 145:341-355.
62. Luc G, Fievet C, Arveiler D, et al. Apolipoproteins C-III and E in apoB- and nonapoB-containing lipoproteins in two populations at contrasting risk for myocardial infarction: the ECTIM study. Etude Cas Temoins sur Infarctus du Myocarde. J Lipid Res 1996; 37:508-517.
63. Kawakami A, Aikawa M, Libby P, et al. Apolipoprotein CIII in apolipoprotein B lipoproteins enhances the adhesion of human monocytic cells to endothelial cells. Circulation 2006; 113:691-700.
64. Kawakami A, Aikawa M, Alcaide P, et al. Apolipoprotein CIII induces expression of vascular cell adhesion molecule-1 in vascular endothelial cells and increases adhesion of monocytic cells. Circulation 2006; 114:681-687.
65. Kawakami A, Osaka M, Tani M, et al. Apolipoprotein CIII links hyperlipidemia with vascular endothelial cell dysfunction. Circulation 2008; 118:731-742.
66. Olivieri O, Martinelli N, Baroni M, et al. Factor II activity is similarly increased in patients with elevated apolipoprotein CIII and in carriers of the factor II 20210A allele. J Am Heart Assoc 2013; 2:e000440.
67. Zheng C, Azcutia V, Aikawa E, et al. Statins suppress apolipoprotein CIIIinduced vascular endothelial cell activation and monocyte adhesion. Eur Heart J 2013; 34:615-624.
68. Briones ER, Mao SJ, Palumbo PJ, et al. Analysis of plasma lipids and apolipoproteins in insulin-dependent and noninsulin-dependent diabetics. Metabolism 1984; 33:42-49.
69. Juntti-Berggren L, Refai E, Appelskog I, et al. Apolipoprotein CIII promotes Ca2-dependent beta cell death in type 1 diabetes. Proc Natl Acad Sci U S A 2004; 101:10090-10094.
70. Holmberg R, Refai E, Höög A, et al. Lowering apolipoprotein CIII delays onset of type 1 diabetes. Proc Natl Acad Sci U S A 2011; 108:10685-10689.
71. Sol EM, Sundsten T, Bergsten P. Role of MAPK in apolipoprotein CIII-induced apoptosis in INS-1E cells. Lipids Health Dis 2009; 8:3.
72. Hokanson JE, Kinney GL, Cheng S, et al. Susceptibility to type 1 diabetes is associated with ApoCIII gene haplotypes. Diabetes 2006; 55:834-838.
73. Strling J, Juntti-Berggren L, Olivecrona G, et al. Apolipoprotein CIII reduces proinflammatory cytokine-induced apoptosis in rat pancreatic islets via the Akt prosurvival pathway. Endocrinology 2011; 152:3040-3048.
74. Graham MJ, Lee RG, Bell TA, et al. Antisense oligonucleotide inhibition of apolipoprotein C-III reduces plasma triglycerides in rodents, nonhuman primates, and humans. Circ Res 2013; 112:1479-1490.
75. Caron S, Verrijken A, Mertens I, et al. Transcriptional activation of apolipoprotein CIII expression by glucose may contribute to diabetic dyslipidemia. Arterioscler Thromb Vasc Biol 2011; 31:513-519.
76. Chen M, Breslow J, Li W, Leff T. Transcriptional regulation of the apoC-III gene by insulin in diabetic mice: correlation with changes in plasma triglyceride levels. J Lipid Res 1994; 35:1918-1924.
77. Staels B, Vu-Dac N, Kosykh VA, et al. Fibrates downregulate apolipoprotein C-III expression independent of induction of peroxisomal acyl coenzyme A oxidase. A potential mechanism for the hypolipidemic action of fibrates. J Clin Invest 1995; 95:705-712.
78. Forcheron F, Cachefo A, Thevenon S, et al. Mechanisms of the triglycerideand cholesterol-lowering effect of fenofibrate in hyperlipidemic type 2 diabetic patients. Diabetes 2002; 51:3486-3491.
79. Tso P, Drake DS, Black DD, Sabesin SM. Evidence for separate pathways of chylomicron and very low-density lipoprotein assembly and transport by rat small intestine. Am J Physiol 1984; 247:G599-610.
80. Siddiqi S, Saleem U, Abumrad NA, et al. A novel multiprotein complex is required to generate the prechylomicron transport vesicle from intestinal ER. J Lipid Res 2010; 51:1918-1928.
81. Xiao C, Hsieh J, Adeli K, Lewis GF. Gut-liver interaction in triglyceride-rich lipoprotein metabolism. Am J Physiol Endocrinol Metab 2011; 301:E429-E446.