Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Current Atherosclerosis Reports
Published in: Current Atherosclerosis Reports 8/2019

Open Access 01-08-2019 | Lipolysis | Nonstatin Drugs (R. Carmena, Section Editor)

Emerging Evidence that ApoC-III Inhibitors Provide Novel Options to Reduce the Residual CVD

Authors: Marja-Riitta Taskinen, Chris J. Packard, Jan Borén

Published in: Current Atherosclerosis Reports | Issue 8/2019

Login to get access

Abstract

Purpose of Review

Apolipoprotein C-III (apoC-III) is known to inhibit lipoprotein lipase (LPL) and function as an important regulator of triglyceride metabolism. In addition, apoC-III has also more recently been identified as an important risk factor for cardiovascular disease. This review summarizes the mechanisms by which apoC-III induces hypertriglyceridemia and promotes atherogenesis, as well as the findings from recent clinical trials using novel strategies for lowering apoC-III.

Recent Findings

Genetic studies have identified subjects with heterozygote loss-of-function (LOF) mutations in APOC3, the gene coding for apoC-III. Clinical characterization of these individuals shows that the LOF variants associate with a low-risk lipoprotein profile, in particular reduced plasma triglycerides. Recent results also show that complete deficiency of apoC-III is not a lethal mutation and is associated with very rapid lipolysis of plasma triglyceride-rich lipoproteins (TRL). Ongoing trials based on emerging gene-silencing technologies show that intervention markedly lowers apoC-III levels and, consequently, plasma triglyceride. Unexpectedly, the evidence points to apoC-III not only inhibiting LPL activity but also suppressing removal of TRLs by LPL-independent pathways.

Summary

Available data clearly show that apoC-III is an important cardiovascular risk factor and that lifelong deficiency of apoC-III is cardioprotective. Novel therapies have been developed, and results from recent clinical trials indicate that effective reduction of plasma triglycerides by inhibition of apoC-III might be a promising strategy in management of severe hypertriglyceridemia and, more generally, a novel approach to CHD prevention in those with elevated plasma triglyceride.
Literature
1.
Gangabadage CS, Zdunek J, Tessari M, Nilsson S, Olivecrona G, Wijmenga SS. Structure and dynamics of human apolipoprotein CIII. J Biol Chem. 2008;283(25):17416–27.PubMedCrossRef
2.
Liu H, Talmud PJ, Lins L, Brasseur R, Olivecrona G, Peelman F, et al. Characterization of recombinant wild type and site-directed mutations of apolipoprotein C-III: lipid binding, displacement of ApoE, and inhibition of lipoprotein lipase. Biochemistry. 2000;39(31):9201–12.PubMedCrossRef
3.
Sparrow JT, Pownall HJ, Hsu FJ, Blumenthal LD, Culwell AR, Gotto AM. Lipid binding by fragments of apolipoprotein C-III-1 obtained by thrombin cleavage. Biochemistry. 1977;16(25):5427–31.PubMedCrossRef
4.
Lins L, Flore C, Chapelle L, Talmud PJ, Thomas A, Brasseur R. Lipid-interacting properties of the N-terminal domain of human apolipoprotein C-III. Protein Eng. 2002;15(6):513–20.PubMedCrossRef
5.
Meyers NL, Larsson M, Vorrsjo E, Olivecrona G, Small DM. Aromatic residues in the C terminus of apolipoprotein C-III mediate lipid binding and LPL inhibition. J Lipid Res. 2017;58(5):840–52.PubMedPubMedCentralCrossRef
6.
Trenchevska O, Schaab MR, Nelson RW, Nedelkov D. Development of multiplex mass spectrometric immunoassay for detection and quantification of apolipoproteins C-I, C-II, C-III and their proteoforms. Methods. 2015;81:86–92.PubMedPubMedCentralCrossRef
7.
• Olivieri O, Chiariello C, Martinelli N, Castagna A, Speziali G, Girelli D, et al. Sialylated isoforms of apolipoprotein C-III and plasma lipids in subjects with coronary artery disease. Clin Chem Lab Med. 2018;56(9):1542–50 Shows that specific patterns of apoC-III glycoforms are present across different total apoC-III concentrations in CAD patients. The inhibitory effect of ApoC-III on LPL appears related to total apoC-III concentration, but not to the relative proportion of apoC-III glycoforms. PubMedCrossRef
8.
Boren J, Watts GF, Adiels M, Soderlund S, Chan DC, Hakkarainen A, et al. Kinetic and related determinants of plasma triglyceride concentration in abdominal obesity: multicenter tracer kinetic study. Arterioscler Thromb Vasc Biol. 2015;35(10):2218–24.PubMedCrossRef
9.
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(15):1722–34.PubMedPubMedCentralCrossRef
10.
Yao Z. Human apolipoprotein C-III - a new intrahepatic protein factor promoting assembly and secretion of very low density lipoproteins. Cardiovasc Hematol Disord Drug Targets. 2012;12(2):133–40.PubMedCrossRef
11.
Taskinen MR, Boren J. New insights into the pathophysiology of dyslipidemia in type 2 diabetes. Atherosclerosis. 2015;239(2):483–95.PubMedCrossRef
12.
Adiels M, Olofsson SO, Taskinen MR, Boren J. Overproduction of very low-density lipoproteins is the hallmark of the dyslipidemia in the metabolic syndrome. Arterioscler Thromb Vasc Biol. 2008;28(7):1225–36.PubMedCrossRef
13.
Graham MJ, Lee RG, Bell TA 3rd, Fu W, Mullick AE, Alexander VJ, et al. Antisense oligonucleotide inhibition of apolipoprotein C-III reduces plasma triglycerides in rodents, nonhuman primates, and humans. Circ Res. 2013;112(11):1479–90.PubMedCrossRef
14.
• Reyes-Soffer G, Sztalryd C, Horenstein RB, Holleran S, Matveyenko A, Thomas T, et al. Effects of APOC3 heterozygous deficiency on plasma lipid and lipoprotein metabolism. Arterioscler Thromb Vasc Biol. 2019;39(1):63–72 The physiological effects of 50% reductions in plasma apoC-III resulting from heterozygosity for a naturally occurring APOC3 LOF mutation resulted in higher rates of lipolysis of VLDL-TG and higher rates of conversion of VLDL to LDL. No changes were detected in remnant removal of VLDL remnants by the liver or in rates of secretion of VLDL. PubMedCrossRefPubMedCentral
15.
• Ramms B, Gordts P. Apolipoprotein C-III in triglyceride-rich lipoprotein metabolism. Curr Opin Lipidol. 2018;29(3):171–9 Excellent recent review. PubMedCrossRef
16.
Ebara T, Ramakrishnan R, Steiner G, Shachter NS. Chylomicronemia due to apolipoprotein CIII overexpression in apolipoprotein E-null mice. Apolipoprotein CIII-induced hypertriglyceridemia is not mediated by effects on apolipoprotein E. J Clin Invest. 1997;99(11):2672–81.PubMedPubMedCentralCrossRef
17.
Lambert DA, Smith LC, Pownall H, Sparrow JT, Nicolas JP, Gotto AM Jr. Hydrolysis of phospholipids by purified milk lipoprotein lipase. Effect of apoprotein CII, CIII, A and E, and synthetic fragments. Clin Chim Acta. 2000;291(1):19–33.PubMedCrossRef
18.
Sacks FM. The crucial roles of apolipoproteins E and C-III in apoB lipoprotein metabolism in normolipidemia and hypertriglyceridemia. Curr Opin Lipidol. 2015;26(1):56–63.PubMedPubMedCentralCrossRef
19.
Campos H, Perlov D, Khoo C, Sacks FM. Distinct patterns of lipoproteins with apoB defined by presence of apoE or apoC-III in hypercholesterolemia and hypertriglyceridemia. J Lipid Res. 2001;42(8):1239–49.PubMedCrossRef
20.
Narayanaswami V, Ryan RO. Molecular basis of exchangeable apolipoprotein function. Biochim Biophys Acta. 2000;1483(1):15–36.PubMedCrossRef
21.
Olin-Lewis K, Krauss RM, La Belle M, Blanche PJ, Barrett PH, Wight TN, et al. ApoC-III content of apoB-containing lipoproteins is associated with binding to the vascular proteoglycan biglycan. J Lipid Res. 2002;43(11):1969–77.PubMedCrossRef
22.
Davidsson P, Hulthe J, Fagerberg B, Olsson BM, Hallberg C, Dahllof B, et al. A proteomic study of the apolipoproteins in LDL subclasses in patients with the metabolic syndrome and type 2 diabetes. J Lipid Res. 2005;46(9):1999–2006.PubMedCrossRef
23.
Hiukka A, Stahlman M, Pettersson C, Levin M, Adiels M, Teneberg S, et al. ApoCIII-enriched LDL in type 2 diabetes displays altered lipid composition, increased susceptibility for sphingomyelinase, and increased binding to biglycan. Diabetes. 2009;58(9):2018–26.PubMedPubMedCentralCrossRef
24.
Boren J, Gustafsson M, Skalen K, Flood C, Innerarity TL. Role of extracellular retention of low density lipoproteins in atherosclerosis. Curr Opin Lipidol. 2000;11(5):451–6.PubMedCrossRef
25.
Gustafsson M, Boren J. Mechanism of lipoprotein retention by the extracellular matrix. Curr Opin Lipidol. 2004;15(5):505–14.PubMedCrossRef
26.
Gustafsson M, Flood C, Jirholt P, Boren J. Retention of atherogenic lipoproteins in atherogenesis. Cell Mol Life Sci. 2004;61(1):4–9.PubMedCrossRef
27.
Segrest J, Jones M, Mishra V, Pierotti V, Young S, Boren J, et al. Apolipoprotein B-100: conservation of lipid-associating amphipathic secondary structural motifs in nine species of vertebrates. J Lipid Res. 1998;3:85–102.CrossRef
28.
Schissel SL, Jiang X, Tweedie-Hardman J, Jeong T, Camejo EH, Najib J, et al. Secretory sphingomyelinase, a product of the acid sphingomyelinase gene, can hydrolyze atherogenic lipoproteins at neutral pH. Implications for atherosclerotic lesion development. J Biol Chem. 1998;273(5):2738–46.PubMedCrossRef
29.
• Ruuth M, Nguyen SD, Vihervaara T, Hilvo M, Laajala TD, Kondadi PK, et al. Susceptibility of low-density lipoprotein particles to aggregate depends on particle lipidome, is modifiable, and associates with future cardiovascular deaths. Eur Heart J. 2018;39(27):2562–73 Aggregation-prone LDL was found to predict death from cardiovascular causes independent of conventional atherosclerosis risk factors. PubMedPubMedCentralCrossRef
30.
Kawakami A, Aikawa M, Alcaide P, Luscinskas FW, Libby P, Sacks FM. Apolipoprotein CIII induces expression of vascular cell adhesion molecule-1 in vascular endothelial cells and increases adhesion of monocytic cells. Circulation. 2006;114(7):681–7.PubMedCrossRef
31.
Kawakami A, Aikawa M, Nitta N, Yoshida M, Libby P, Sacks FM. Apolipoprotein CIII-induced THP-1 cell adhesion to endothelial cells involves pertussis toxin-sensitive G protein- and protein kinase C alpha-mediated nuclear factor-kappaB activation. Arterioscler Thromb Vasc Biol. 2007;27(1):219–25.PubMedCrossRef
32.
• Liu DJ, Peloso GM, Yu H, Butterworth AS, Wang X, Mahajan A, et al. Exome-wide association study of plasma lipids in > 300,000 individuals. Nat Genet. 2017;49(12):1758–66 The authors screened variants on an exome-focused genotyping array in >300,000 participants and identified 444 independent variants in 250 loci significantly associated with total cholesterol, HDL-C), LDL-C and/or plasma triglycerides. PubMedPubMedCentralCrossRef
33.
• Klarin D, Damrauer SM, Cho K, Sun YV, Teslovich TM, Honerlaw J, et al. Genetics of blood lipids among ~300,000 multi-ethnic participants of the Million Veteran Program. Nat Genet. 2018;50(11):1514–23 The authors tested in 297,626 veterans up to around 32 million variants for association with lipid levels and identified 118 novel genome-wide significant loci after meta-analysis with data from the Global Lipids Genetics Consortium (total n > 600,000). PubMedPubMedCentralCrossRef
34.
35.
Bernelot Moens SJ, van Capelleveen JC, Stroes ES. Inhibition of ApoCIII: the next PCSK9? Curr Opin Lipidol. 2014;25(6):418–22.PubMedCrossRef
36.
Pollin TI, Damcott CM, Shen H, Ott SH, Shelton J, Horenstein RB, et al. A null mutation in human APOC3 confers a favorable plasma lipid profile and apparent cardioprotection. Science. 2008;322(5908):1702–5.PubMedPubMedCentralCrossRef
37.
• Tachmazidou I, Dedoussis G, Southam L, Farmaki AE, Ritchie GR, Xifara DK, et al. A rare functional cardioprotective APOC3 variant has risen in frequency in distinct population isolates. Nat Commun. 2013;4:2872 The authors demonstrate significant evidence for association between R19X, a functional variant in APOC3, with increased HDL-C and decreased triglycerides levels.PubMedCrossRef
38.
Crawford DC, Dumitrescu L, Goodloe R, Brown-Gentry K, Boston J, McClellan B Jr, 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 study. Circ Cardiovasc Genet. 2014;7(6):848–53.PubMedPubMedCentralCrossRef
39.
Muddyman D, Smee C, Griffin H, Kaye J. Implementing a successful data-management framework: the UK10K managed access model. Genome Med. 2013;5(11):100.PubMedPubMedCentralCrossRef
40.
Bochem AE, van Capelleveen JC, Dallinga-Thie GM, Schimmel AW, Motazacker MM, Tietjen I, et al. Two novel mutations in apolipoprotein C3 underlie atheroprotective lipid profiles in families. Clin Genet. 2014;85(5):433–40.PubMedCrossRef
41.
Liu H, Labeur C, Xu CF, Ferrell R, Lins L, Brasseur R, et al. Characterization of the lipid-binding properties and lipoprotein lipase inhibition of a novel apolipoprotein C-III variant Ala23Thr. J Lipid Res. 2000;41(11):1760–71.PubMedCrossRef
42.
Sundaram M, Curtis KR, Amir Alipour M, LeBlond ND, Margison KD, Yaworski RA, et al. The apolipoprotein C-III (Gln38Lys) variant associated with human hypertriglyceridemia is a gain-of-function mutation. J Lipid Res. 2017;58(11):2188–96.PubMedPubMedCentralCrossRef
43.
• Tg, Hdl Working Group of the Exome Sequencing Project NHL, Blood I, Crosby J, Peloso GM, Auer PL, et al. Loss-of-function mutations in APOC3, triglycerides, and coronary disease. N Engl J Med. 2014;371(1):22–31 Rare mutations that disrupt APOC3 function were associated with lower levels of plasma triglycerides and APOC3. Carriers of these mutations were found to have a reduced risk of coronary heart disease.CrossRef
44.
• Jorgensen AB, Frikke-Schmidt R, Nordestgaard BG, Tybjaerg-Hansen A. Loss-of-function mutations in APOC3 and risk of ischemic vascular disease. N Engl J Med. 2014;371(1):32–41 Loss-of-function mutations in APOC3 were associated with low levels of triglycerides and a reduced risk of ischemic cardiovascular disease. PubMedCrossRef
45.
Wulff AB, Nordestgaard BG, Tybjaerg-Hansen A. APOC3 loss-of-function mutations, remnant cholesterol, low-density lipoprotein cholesterol, and cardiovascular risk: mediation- and meta-analyses of 137 895 individuals. Arterioscler Thromb Vasc Biol. 2018;38(3):660–8.PubMedCrossRef
46.
• Ference BA, Kastelein JJP, Ray KK, Ginsberg HN, Chapman MJ, Packard CJ, et al. Association of triglyceride-lowering LPL variants and LDL-C-lowering LDLR variants with risk of coronary heart disease. JAMA. 2019;321(4):364–73 Triglyceride-lowering LPL variants and LDL-C-lowering LDLR variants were associated with similar lower risk of CHD per unit difference in ApoB. Therefore, the clinical benefit of lowering triglyceride and LDL-C levels may be proportional to the absolute change in ApoB. PubMedCrossRefPubMedCentral
47.
• Saleheen D, Natarajan P, Armean IM, Zhao W, Rasheed A, Khetarpal SA, et al. Human knockouts and phenotypic analysis in a cohort with a high rate of consanguinity. Nature. 2017;544(7649):235–9 The authors identified individuals carrying homozygous predicted LOF mutations, and performed detailed phenotypic analysis. PubMedPubMedCentralCrossRef
48.
Shih HM, Liu Z, Towle HC. Two CACGTG motifs with proper spacing dictate the carbohydrate regulation of hepatic gene transcription. J Biol Chem. 1995;270(37):21991–7.PubMedCrossRef
49.
Caron S, Verrijken A, Mertens I, Samanez CH, Mautino G, Haas JT, et al. Transcriptional activation of apolipoprotein CIII expression by glucose may contribute to diabetic dyslipidemia. Arterioscler Thromb Vasc Biol. 2011;31(3):513–9.PubMedCrossRef
50.
Altomonte J, Cong L, Harbaran S, Richter A, Xu J, Meseck M, et al. Foxo1 mediates insulin action on apoC-III and triglyceride metabolism. J Clin Invest. 2004;114(10):1493–503.PubMedPubMedCentralCrossRef
51.
Chen M, Breslow JL, 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(11):1918–24.PubMedCrossRef
52.
Taskinen MR, Boren J. Why is apolipoprotein CIII emerging as a novel therapeutic target to reduce the burden of cardiovascular disease? Curr Atheroscler Rep. 2016;18(10):59.PubMedPubMedCentralCrossRef
53.
Choo VL, Viguiliouk E, Blanco Mejia S, Cozma AI, Khan TA, Ha V, et al. Food sources of fructose-containing sugars and glycaemic control: systematic review and meta-analysis of controlled intervention studies. BMJ. 2018;363:k4644.PubMedPubMedCentralCrossRef
54.
Huff MW, Nestel PJ. Metabolism of apolipoproteins CII, CIII1, CIII2 and VLDL-B in human subjects consuming high carbohydrate diets. Metabolism. 1982;31(5):493–8.PubMedCrossRef
55.
Archer WR, Desroches S, Lamarche B, Deriaz O, Landry N, Fontaine-Bisson B, et al. Variations in plasma apolipoprotein C-III levels are strong correlates of the triglyceride response to a high-monounsaturated fatty acid diet and a high-carbohydrate diet. Metabolism. 2005;54(10):1390–7.PubMedCrossRef
56.
Furtado JD, Campos H, Appel LJ, Miller ER, Laranjo N, Carey VJ, et al. Effect of protein, unsaturated fat, and carbohydrate intakes on plasma apolipoprotein B and VLDL and LDL containing apolipoprotein C-III: results from the OmniHeart trial. Am J Clin Nutr. 2008;87(6):1623–30.PubMedCrossRef
57.
Shin MJ, Blanche PJ, Rawlings RS, Fernstrom HS, Krauss RM. Increased plasma concentrations of lipoprotein(a) during a low-fat, high-carbohydrate diet are associated with increased plasma concentrations of apolipoprotein C-III bound to apolipoprotein B-containing lipoproteins. Am J Clin Nutr. 2007;85(6):1527–32.PubMedCrossRef
58.
Mendoza S, Trenchevska O, King SM, Nelson RW, Nedelkov D, Krauss RM, et al. Changes in low-density lipoprotein size phenotypes associate with changes in apolipoprotein C-III glycoforms after dietary interventions. J Clin Lipidol. 2017;11(1):224–33 e2.PubMedCrossRef
59.
Taskinen MR, Soderlund S, Bogl LH, Hakkarainen A, Matikainen N, Pietilainen KH, et al. Adverse effects of fructose on cardiometabolic risk factors and hepatic lipid metabolism in subjects with abdominal obesity. J Intern Med. 2017;282(2):187–201.PubMedCrossRef
60.
Stanhope KL, Medici V, Bremer AA, Lee V, Lam HD, Nunez MV, et al. A dose-response study of consuming high-fructose corn syrup-sweetened beverages on lipid/lipoprotein risk factors for cardiovascular disease in young adults. Am J Clin Nutr. 2015;101(6):1144–54.PubMedPubMedCentralCrossRef
61.
Schwarz JM, Noworolski SM, Erkin-Cakmak A, Korn NJ, Wen MJ, Tai VW, et al. Effects of dietary fructose restriction on liver fat, De novo lipogenesis, and insulin kinetics in children with obesity. Gastroenterology. 2017;153(3):743–52.PubMedCrossRef
62.
• Mardinoglu A, Wu H, Bjornson E, Zhang C, Hakkarainen A, Rasanen SM, et al. An integrated understanding of the rapid metabolic benefits of a carbohydrate-restricted diet on hepatic steatosis in humans. Cell Metab. 2018;27(3):559–71 e5 Showing that dietary carbohydrate reduction induces marked reduction in plasma triglycerides linked to reduced apoC-III levels. PubMedCrossRefPubMedCentral
63.
Pavlic M, Valero R, Duez H, Xiao C, Szeto L, Patterson BW, et al. Triglyceride-rich lipoprotein-associated apolipoprotein C-III production is stimulated by plasma free fatty acids in humans. Arterioscler Thromb Vasc Biol. 2008;28(9):1660–5.PubMedPubMedCentralCrossRef
64.
Faghihnia N, Mangravite LM, Chiu S, Bergeron N, Krauss RM. Effects of dietary saturated fat on LDL subclasses and apolipoprotein CIII in men. Eur J Clin Nutr. 2012;66(11):1229–33.PubMedPubMedCentralCrossRef
65.
Balk EM, Lichtenstein AH. Omega-3 fatty acids and cardiovascular disease: summary of the 2016 Agency of Healthcare Research and Quality Evidence Review. Nutrients. 2017;9(8).PubMedCentralCrossRef
66.
Sahebkar A, Simental-Mendia LE, Mikhailidis DP, Pirro M, Banach M, Sirtori CR, et al. Effect of omega-3 supplements on plasma apolipoprotein C-III concentrations: a systematic review and meta-analysis of randomized controlled trials. Ann Med. 2018;50(7):565–75.PubMedCrossRef
67.
• Morton AM, Furtado JD, Lee J, Amerine W, Davidson MH, Sacks FM. The effect of omega-3 carboxylic acids on apolipoprotein CIII-containing lipoproteins in severe hypertriglyceridemia. J Clin Lipidol. 2016;10(6):1442–51 e4 Omega-3 carboxylic acids may reduce triglyceride levels by reducing apoC-III on lipoprotein particle surface.PubMedCrossRef
68.
Oscarsson J, Hurt-Camejo E. 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. 2017;16(1):149.PubMedPubMedCentralCrossRef
69.
Hertz R, Bishara-Shieban J, Bar-Tana J. Mode of action of peroxisome proliferators as hypolipidemic drugs. Suppression of apolipoprotein C-III. J Biol Chem. 1995;270(22):13470–5.PubMedCrossRef
70.
Ito Y, Azrolan N, O'Connell A, Walsh A, Breslow JL. Hypertriglyceridemia as a result of human apo CIII gene expression in transgenic mice. Science. 1990;249(4970):790–3.PubMedCrossRef
71.
Staels B, Vu-Dac N, Kosykh VA, Saladin R, Fruchart JC, Dallongeville J, 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(2):705–12.PubMedPubMedCentralCrossRef
72.
Aalto-Setala K, Fisher EA, Chen X, Chajek-Shaul T, Hayek T, Zechner R, et al. Mechanism of hypertriglyceridemia in human apolipoprotein (apo) CIII transgenic mice. Diminished very low density lipoprotein fractional catabolic rate associated with increased apo CIII and reduced apo E on the particles. J Clin Invest. 1992;90(5):1889–900.PubMedPubMedCentralCrossRef
73.
Bougarne N, Weyers B, Desmet SJ, Deckers J, Ray DW, Staels B, et al. Molecular actions of PPARalpha in lipid metabolism and inflammation. Endocr Rev. 2018;39(5):760–802.PubMedCrossRef
74.
Haubenwallner S, Essenburg AD, Barnett BC, Pape ME, DeMattos RB, Krause BR, et al. Hypolipidemic activity of select fibrates correlates to changes in hepatic apolipoprotein C-III expression: a potential physiologic basis for their mode of action. J Lipid Res. 1995;36(12):2541–51.PubMedCrossRef
75.
Reyes-Soffer G, Ngai CI, Lovato L, Karmally W, Ramakrishnan R, Holleran S, et al. Effect of combination therapy with fenofibrate and simvastatin on postprandial lipemia in the ACCORD lipid trial. Diabetes Care. 2013;36(2):422–8.PubMedPubMedCentralCrossRef
76.
Attia N, Durlach V, Cambilleau M, Roche D, Girard-Globa A. Postprandial concentrations and distribution of apo C-III in type 2 diabetic patients. Effect of bezafibrate treatment. Atherosclerosis. 2000;149(2):427–33.PubMedCrossRef
77.
Lemieux I, Salomon H, Despres JP. Contribution of apo CIII reduction to the greater effect of 12-week micronized fenofibrate than atorvastatin therapy on triglyceride levels and LDL size in dyslipidemic patients. Ann Med. 2003;35(6):442–8.PubMedCrossRef
78.
de Man FH, de Beer F, van der Laarse A, Jansen H, Leuven JA, Souverijn JH, et al. The hypolipidemic action of bezafibrate therapy in hypertriglyceridemia is mediated by upregulation of lipoprotein lipase: no effects on VLDL substrate affinity to lipolysis or LDL receptor binding. Atherosclerosis. 2000;153(2):363–71.PubMedCrossRef
79.
Chan DC, Watts GF, Ooi EM, Ji J, Johnson AG, Barrett PH. Atorvastatin and fenofibrate have comparable effects on VLDL-apolipoprotein C-III kinetics in men with the metabolic syndrome. Arterioscler Thromb Vasc Biol. 2008;28(10):1831–7.PubMedPubMedCentralCrossRef
80.
Nagashima K, Lopez C, Donovan D, Ngai C, Fontanez N, Bensadoun A, et al. Effects of the PPARgamma agonist pioglitazone on lipoprotein metabolism in patients with type 2 diabetes mellitus. J Clin Invest. 2005;115(5):1323–32.PubMedPubMedCentralCrossRef
81.
Wagner JA, Larson PJ, Weiss S, Miller JL, Doebber TW, Wu MS, et al. Individual and combined effects of peroxisome proliferator-activated receptor and {gamma} agonists, fenofibrate and rosiglitazone, on biomarkers of lipid and glucose metabolism in healthy nondiabetic volunteers. J Clin Pharmacol. 2005;45(5):504–13.PubMedCrossRef
82.
Hernandez C, Molusky M, Li Y, Li S, Lin JD. Regulation of hepatic ApoC3 expression by PGC-1beta mediates hypolipidemic effect of nicotinic acid. Cell Metab. 2010;12(4):411–9.PubMedPubMedCentralCrossRef
83.
Ooi EM, Watts GF, Chan DC, Chen MM, Nestel PJ, Sviridov D, et al. Dose-dependent effect of rosuvastatin on VLDL-apolipoprotein C-III kinetics in the metabolic syndrome. Diabetes Care. 2008;31(8):1656–61.PubMedPubMedCentralCrossRef
84.
Sahebkar A, Simental-Mendia LE, Mikhailidis DP, Pirro M, Banach M, Sirtori CR, et al. Effect of statin therapy on plasma apolipoprotein CIII concentrations: a systematic review and meta-analysis of randomized controlled trials. J Clin Lipidol. 2018;12(3):801–9.PubMedCrossRef
85.
Maki KC, Bays HE, Dicklin MR, Johnson SL, Shabbout M. Effects of prescription omega-3-acid ethyl esters, coadministered with atorvastatin, on circulating levels of lipoprotein particles, apolipoprotein CIII, and lipoprotein-associated phospholipase A2 mass in men and women with mixed dyslipidemia. J Clin Lipidol. 2011;5(6):483–92.PubMedCrossRef
86.
Dunbar RL, Nicholls SJ, Maki KC, Roth EM, Orloff DG, Curcio D, et al. Effects of omega-3 carboxylic acids on lipoprotein particles and other cardiovascular risk markers in high-risk statin-treated patients with residual hypertriglyceridemia: a randomized, controlled, double-blind trial. Lipids Health Dis. 2015;14:98.PubMedPubMedCentralCrossRef
87.
Ballantyne CM, Bays HE, Braeckman RA, Philip S, Stirtan WG, Doyle RT Jr, et al. Icosapent ethyl (eicosapentaenoic acid ethyl ester): effects on plasma apolipoprotein C-III levels in patients from the MARINE and ANCHOR studies. J Clin Lipidol. 2016;10(3):635–45 e1.PubMedCrossRef
88.
Bhatt DL, Steg PG, Miller M, Brinton EA, Jacobson TA, Ketchum SB, et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med. 2019;380(1):11–22.PubMedCrossRef
89.
Group ASC, Bowman L, Mafham M, Wallendszus K, Stevens W, Buck G, et al. Effects of n-3 fatty acid supplements in diabetes mellitus. N Engl J Med. 2018;379(16):1540–50.CrossRef
90.
Gouni-Berthold I. The role of antisense oligonucleotide therapy against apolipoprotein-CIII in hypertriglyceridemia. Atheroscler Suppl. 2017;30:19–27.PubMedCrossRef
91.
Watts JK, Corey DR. Silencing disease genes in the laboratory and the clinic. J Pathol. 2012;226(2):365–79.PubMedCrossRef
92.
93.
94.
Bernards R. Exploring the uses of RNAi--gene knockdown and the Nobel prize. N Engl J Med. 2006;355(23):2391–3.PubMedCrossRef
95.
Crooke ST, Witztum JL, Bennett CF, Baker BF. RNA-targeted therapeutics. Cell Metab. 2018;27(4):714–39.PubMedCrossRef
96.
97.
Schmidt K, Prakash TP, Donner AJ, Kinberger GA, Gaus HJ, Low A, et al. Characterizing the effect of GalNAc and phosphorothioate backbone on binding of antisense oligonucleotides to the asialoglycoprotein receptor. Nucleic Acids Res. 2017;45(5):2294–306.PubMedPubMedCentralCrossRef
98.
• Gaudet D, Brisson D, Tremblay K, Alexander VJ, Singleton W, Hughes SG, et al. Targeting APOC3 in the familial chylomicronemia syndrome. N Engl J Med. 2014;371(23):2200–6 The authors administered an inhibitor of APOC3 mRNA to treat three patients with the familial chylomicronemia syndrome and severe hypertriglyceridemia. Results support the role of APOC3 as a key regulator of LPL-independent pathways of triglyceride metabolism.PubMedCrossRef
99.
• Gordts PL, Nock R, Son NH, Ramms B, Lew I, Gonzales JC, et al. ApoC-III inhibits clearance of triglyceride-rich lipoproteins through LDL family receptors. J Clin Invest. 2016;126(8):2855–66 Demonstrates that apoC-III ASO reduced plasma triglycerides in mice lacking HSPG but not when lacking LDLR and LRP1. PubMedPubMedCentralCrossRef
100.
Yang X, Lee SR, Choi YS, Alexander VJ, Digenio A, Yang Q, et al. Reduction in lipoprotein-associated apoC-III levels following volanesorsen therapy: phase 2 randomized trial results. J Lipid Res. 2016;57(4):706–13.PubMedPubMedCentralCrossRef
101.
• Gaudet D, Alexander VJ, Baker BF, Brisson D, Tremblay K, Singleton W, et al. Antisense inhibition of apolipoprotein C-III in patients with hypertriglyceridemia. N Engl J Med. 2015;373(5):438–47 APOC3 antisense intervention induced significant lowering of triglyceride levels, among patients with a broad range of baseline levels. PubMedCrossRef
102.
Digenio A, Dunbar RL, Alexander VJ, Hompesch M, Morrow L, Lee RG, 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.PubMedCrossRef
103.
Blom DJ, O'Dea L, Digenio A, Alexander VJ, Karwatowska-Prokopczuk E, Williams KR, et al. Characterizing familial chylomicronemia syndrome: baseline data of the APPROACH study. J Clin Lipidol. 2018;12(5):1234–43 e5.PubMedCrossRef
104.
Gelrud A, Digenio A, Alexander V, Williams K, Hsieh A, Gouni-Berthold I, et al. Treatment with Volanesorsen (VLN) reduced triglycerides and pancreatitis in patients with FCS and sHTG vs placebo: results of the APPROACH and COMPASS. J Clin Lipidol. 2018;12(2):537.CrossRef
105.
Warden BA, Duell PB. Volanesorsen for treatment of patients with familial chylomicronemia syndrome. Drugs Today (Barc). 2018;54(12):721–35.CrossRef
106.
• Khetarpal SA, Zeng X, Millar JS, Vitali C, Somasundara AVH, Zanoni P, et al. A human APOC3 missense variant and monoclonal antibody accelerate apoC-III clearance and lower triglyceride-rich lipoprotein levels. Nat Med. 2017;23(9):1086–94 The Ala43Thr APOC3 missense variant improved renal clearance of apoC-III possibly by impaired interaction of apoC-III with lipoproteins and. Promising concept studies using a mAb targeting apoC-III in circulation. PubMedPubMedCentralCrossRef
107.
Narayanan P, Shen L, Curtis BR, Bourdon MA, Nolan JP, Gupta S, et al. Investigation into the mechanism(s) that leads to platelet decreases in cynomolgus monkeys during administration of ISIS 104838, a 2′-MOE-modified antisense oligonucleotide. Toxicol Sci. 2018;164(2):613–26.PubMedCrossRef
108.
Nikam RR, Gore KR. Journey of siRNA: clinical developments and targeted delivery. Nucleic Acid Ther. 2018;28(4):209–24.PubMedCrossRef
109.
Alexander VJ, Digenio A, Xia S, Hurh E, Hughes S, Geary RS, et al. Inhibition of apolipoprotein C-III with GalNac conjugated antisense drug potently lowers fasting serum apolipoprotein C-III and triglyceride levels in healthy volunteers with elevated triglycerides. J Am Coll Cardiol. 2018;71(11 Supplement):A1724.CrossRef
Metadata
Title
Emerging Evidence that ApoC-III Inhibitors Provide Novel Options to Reduce the Residual CVD
Authors
Marja-Riitta Taskinen
Chris J. Packard
Jan Borén
Publication date
01-08-2019
Publisher
Springer US
Published in
Current Atherosclerosis Reports / Issue 8/2019
Print ISSN: 1523-3804
Electronic ISSN: 1534-6242
DOI
https://doi.org/10.1007/s11883-019-0791-9

Other articles of this Issue 8/2019

Current Atherosclerosis Reports 8/2019 Go to the issue

Emerging Research (S. Virani, Section Editor)

Major Randomized Clinical Trials in Cardiovascular Disease Prevention Presented at the 2019 American College of Cardiology Annual Scientific Session

Cardiovascular Disease and Stroke (S. Prabhakaran, Section Editor)

Anticoagulation Resumption After Stroke from Atrial Fibrillation

Statin Drugs (M. Tikkanen, Section Editor)

Role of Statin Therapy in Primary Prevention of Cardiovascular Disease in Elderly Patients

Nonstatin Drugs (R. Carmena, Section Editor)

Antisense Oligonucleotides Targeting Lipoprotein(a)
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discuss last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discuss last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits