Apolipoprotein C-III
2017; Lippincott Williams & Wilkins; Volume: 37; Issue: 6 Linguagem: Romeno
10.1161/atvbaha.117.309493
ISSN1524-4636
Autores Tópico(s)Lipid metabolism and disorders
ResumoHomeArteriosclerosis, Thrombosis, and Vascular BiologyVol. 37, No. 6Apolipoprotein C-III Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBApolipoprotein C-IIIThe Small Protein With Sizeable Vascular Risk Michael Miller Michael MillerMichael Miller From the Department of Cardiovascular Medicine, University of Maryland School of Medicine and Veterans Affairs Medical Center (VAMC), Baltimore. Originally published1 Jun 2017https://doi.org/10.1161/ATVBAHA.117.309493Arteriosclerosis, Thrombosis, and Vascular Biology. 2017;37:1013–1014Nearly 60 years have transpired since Albrink and Man1 first observed an association between high triglyceride levels and coronary artery disease (CAD). Yet, the mechanisms underlying this association gained minimal traction until 2 decades later2 and even after many years of exhaustive investigative work, remains incompletely understood.3 What has been clearly demonstrated, however, is that triglyceride serves as a primary mammalian energy source and is not directly atherogenic. Furthermore, triglyceride-rich lipoproteins (eg, chylomicrons, very low-density lipoprotein) develop atherogenic characteristics on their conversion to cholesterol-enriched remnant particles. In this issue of ATVB, van Capelleveen et al4 demonstrate that apoC-III also plays a central role in promoting vascular risk.See accompanying article on page 1206Human apoC-III is an 8.8-kDa polypeptide that contains 79 amino acids and is considerably smaller than other major apolipoproteins regulating lipoprotein metabolism, including apoB100 (512 kDa, 4563 amino acids), apoE (34 kDa, 299 amino acids), and apoA1 (45 kDa, 396 amino acids).5 ApoC-III resides on the surface of triglyceride-rich lipoproteins and serves several important metabolic functions. They include triglyceride raising by direct inhibition of lipoprotein lipase6 and via a recently identified lipoprotein lipase–independent mechanism.7 ApoC-III also inhibits hepatic lipase,8 delays clearance of apoB containing particles, and accelerates the conversion of light to dense low-density lipoprotein (LDL) particles.9 These proatherogenic particles gain facilitated entry through the endothelial intima followed by oxidation and uptake by vascular macrophages lining the arterial wall.10Ironically, the clinical relevance of apoC-III in humans was initially uncovered with low triglyceride, rather than hypertriglyceridemia. Specifically, 2 sisters with familial APOA1-C3 deficiency11 exhibited triglyceride levels of 38 and 61 mg/dL (≈50%–75% lower than the median triglyceride during that period), nondetectable apoC-III levels, and increased fractional turnover of very low-density lipoprotein triglyceride consistent with increased lipoprotein lipase activity.12 More recently, very low triglyceride (mean, 31 mg/dL) combined with a 50% reduction in apoC-III levels was discovered in an Amish cohort who had inherited a single defective allele (APOC3. R19X) that also correlated with reduced coronary calcification.13 Carriers of several different rare APOC3 loss-of-function mutations (including R19X) were subsequently found to have low triglyceride and a significantly reduced risk of vascular disease.14,15In contrast, studies examining the effect of apoC-III enrichment in apoB containing lipoproteins (ie, very low-density lipoprotein and LDL) identified increased coronary arteriographic progression and recurrent CAD events.16,17 Among the 2 large prospective studies that previously examined plasma apoC-III levels and CAD risk, one found a significant association with apoC-III enrichment of LDL but not with plasma apoC-III after adjustment for triglyceride.18 In the second study, apoC-III levels in the top quartile at baseline were predictive of cardiovascular death over the 15-year follow-up period.19 However, this effect was attenuated after adjustment for triglyceride and was of borderline statistical significance in the fully adjusted analysis.19 Finally, a recent meta-analysis that incorporated the aforementioned studies found an ≈33% increased risk of CAD for each 5-mg/dL increment in plasma apoC-III levels20 although the vast majority of these studies did not adjust for triglyceride.The study by van Capelleveen et al4 confirms the association between plasma apoC-III levels and incident CAD. Although these effects were attenuated after adjustment for triglyceride, subgroup analysis found apoC-III to remain independently associated with CAD in subjects with high triglyceride (median, >1.7 mmol/L or 150 mg/dL). Interestingly, the combination of high triglyceride and low apoC-III was not associated with increased CAD risk. This supports the concept that high apoC-III may potentiate vascular risk, especially in the setting of hypertriglyceridemia. As illustrated in the Figure, there are at least 3 potential pathways promoting these effects. Inhibition of lipoprotein lipase and hepatic lipase results in delayed clearance of triglyceride-rich lipoproteins and atherogenic remnants, the latter of which are incorporated by vascular macrophages lining the vascular wall. ApoC-III also inhibits removal of large LDL and remnants by inhibiting hepatic lipoprotein receptors that interact with apoB and apoE, culminating in facilitated conversion to smaller proatherogenic particles (eg, small dense LDL). Finally, apoC-III induces proinflammatory cellular signaling by activating vascular cell adhesion molecule-1 and nuclear factor κB.21 In effect, the association between apoC-III and incident CAD reported by van Capelleveen et al4 was largely attributable to increased triglyceride-rich lipoprotein, remnants, sdLDL (small, dense LDL), and high sensitivity C-reactive protein, a biomarker of systemic inflammation.Download figureDownload PowerPointFigure. Potentiation of vascular risk induced by ApoC-III. The 4 molecules of apoC-III on each of the depicted lipoproteins is for illustration purposes only. It is estimated that there are 10 to 20 apoC-III molecules for each low-density lipoprotein (LDL) particle.18 There is only 1 apoB molecule (as depicted) for each lipoprotein particle. CM indicates chylomicron; CMR, chylomicron remnant; HL, hepatic lipase; IDL, intermediate density lipoprotein; LPL, lipoprotein lipase; NF-κB, nuclear factor-κB; sdLDL, small, dense LDL; TRL, triglyceride-rich lipoprotein; VCAM, vascular cell adhesion molecule; VLDL, very low-density lipoprotein; and VLDLR, very low-density lipoprotein receptor.Overall, the current study suggests that high apoC-III levels provide incremental discriminatory power in the assessment of CAD risk, particularly in hypertriglyceridemia states. However, before routine screening for high apoC-III is recommended, it would seemingly be most reasonable to first establish whether lowering triglyceride (+/- apoC-III) reduces CAD risk. Fortunately, ongoing randomized clinical trials are well underway22,23 and together with novel therapies targeting apoC-III7 should move us a step closer to satisfactorily addressing this clinical conundrum in the near future.DisclosuresDr Miller serves on the Steering Committee for the REDUCE IT Study (Reduction of Cardiovascular Events With Icosapent Ethyl-Intervention Trial).FootnotesCorrespondence to Michael Miller, MD, University of Maryland School of Medicine, 110 S. Paca St, Suite 7–124, Baltimore, MD 21201. E-mail [email protected]References1. Albrink MJ, Man EB. Serum triglycerides in coronary artery disease.AMA Arch Intern Med. 1959; 103:4–8.CrossrefMedlineGoogle Scholar2. Zilversmit DB. Atherogenesis: a postprandial phenomenon.Circulation. 1979; 60:473–485.LinkGoogle Scholar3. Miller M, Stone NJ, Ballantyne C, Bittner V, Criqui MH, Ginsberg HN, Goldberg AC, Howard WJ, Jacobson MS, Kris-Etherton PM, Lennie TA, Levi M, Mazzone T, Pennathur S; American Heart Association Clinical Lipidology, Thrombosis, and Prevention Committee of the Council on Nutrition, Physical Activity, and Metabolism; Council on Arteriosclerosis, Thrombosis and Vascular Biology; Council on Cardiovascular Nursing; Council on the Kidney in Cardiovascular Disease. Triglycerides and cardiovascular disease: a scientific statement from the American Heart Association.Circulation. 2011; 123:2292–2333. doi: 10.1161/CIR.0b013e3182160726.LinkGoogle Scholar4. van Capelleveen JC, Bernelot Moens SJ, Yang X, Kastelein JJP, Wareham NJ, Zwinderman AH, Stroes ESG, Witztum JL, Hovingh GK, Khaw K-T, Boekholdt SM, Tsimikas S. Apolipoprotein C-III levels and incident coronary artery disease risk: the EPIC-Norfolk prospective population study.Arterioscler Thromb Vasc Biol. 2017; 37:1206–1212. doi: 10.1161/ATVBAHA.117.309007.LinkGoogle Scholar5. Kwiterovich PO. Lipid, apolipoprotein and lipoprotein metabolism., Kwiterovich PO, ed. In: The Johns Hopkins Textbook of Dyslipidemia. Baltimore, MD: Lippincott, Williams & Wilkins; 2010:1–21.Google Scholar6. Brown WV, Baginsky ML. Inhibition of lipoprotein lipase by an apoprotein of human very low density lipoprotein.Biochem Biophys Res Commun. 1972; 46:375–382.CrossrefMedlineGoogle Scholar7. Gaudet D, Brisson D, Tremblay K, Alexander VJ, Singleton W, Hughes SG, Geary RS, Baker BF, Graham MJ, Crooke RM, Witztum JL. Targeting APOC3 in the familial chylomicronemia syndrome.N Engl J Med. 2014; 371:2200–2206. doi: 10.1056/NEJMoa1400284.CrossrefMedlineGoogle Scholar8. Windler E, Havel RJ. 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.CrossrefMedlineGoogle Scholar9. Mendivil CO, Zheng C, Furtado J, Lel J, Sacks FM. Metabolism of very-low-density lipoprotein and low-density lipoprotein containing apolipoprotein C-III and not other small apolipoproteins.Arterioscler Thromb Vasc Biol. 2010; 30:239–245. doi: 10.1161/ATVBAHA.109.197830.LinkGoogle Scholar10. Mudd JO, Borlaug BA, Johnston PV, Kral BG, Rouf R, Blumenthal RS, Kwiterovich POBeyond low-density lipoprotein cholesterol: defining the role of low-density lipoprotein heterogeneity in coronary artery disease.J Am Coll Cardiol. 2007; 50:1735–1741. doi: 10.1016/j.jacc.2007.07.045.CrossrefMedlineGoogle Scholar11. Norum RA, Lakier JB, Goldstein S, Angel A, Goldberg RB, Block WD, Noffze DK, Dolphin PJ, Edelglass J, Bogorad DD, Alaupovic P. Familial deficiency of apolipoproteins A-I and C-III and precocious coronary-artery disease.N Engl J Med. 1982; 306:1513–1519. doi: 10.1056/NEJM198206243062503.CrossrefMedlineGoogle Scholar12. Ginsberg HN, Le NA, Goldberg IJ, Gibson JC, Rubinstein A, Wang-Iverson P, Norum R, Brown WV. Apolipoprotein B metabolism in subjects with deficiency of apolipoproteins CIII and AI. Evidence that apolipoprotein CIII inhibits catabolism of triglyceride-rich lipoproteins by lipoprotein lipase in vivo.J Clin Invest. 1986; 78:1287–1295. doi: 10.1172/JCI112713.CrossrefMedlineGoogle Scholar13. Pollin TI, Damcott CM, Shen H, Ott SH, Shelton J, Horenstein RB, Post W, McLenithan JC, Bielak LF, Peyser PA, Mitchell BD, Miller M, O'Connell JR, Shuldiner AR. A null mutation in human APOC3 confers a favorable plasma lipid profile and apparent cardioprotection.Science. 2008; 322:1702–1705. doi: 10.1126/science.1161524.CrossrefMedlineGoogle Scholar14. TG and HDL Working Group of the Exome Sequencing Project, National Heart, Lung, and Blood Institute, 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.CrossrefMedlineGoogle Scholar15. Jørgensen AB, Frikke-Schmidt R, Nordestgaard BG, Tybjærg-Hansen A. Loss-of-function mutations in APOC3 and risk of ischemic vascular disease.N Engl J Med. 2014; 371:32–41. doi: 10.1056/NEJMoa1308027.CrossrefMedlineGoogle Scholar16. Blankenhorn DH, Alaupovic P, Wickham E, Chin HP, Azen SP. Prediction of angiographic change in native human coronary arteries and aortocoronary bypass grafts. Lipid and nonlipid factors.Circulation. 1990; 81:470–476.LinkGoogle Scholar17. Sacks FM, Alaupovic P, Moye LA, Cole TG, Sussex B, Stampfer MJ, Pfeffer MA, Braunwald E. 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.LinkGoogle Scholar18. Mendivil CO, Rimm EB, Furtado J, Chiuve SE, Sacks FM. Low-density lipoproteins containing apolipoprotein C-III and the risk of coronary heart disease.Circulation. 2011; 124:2065–2072.LinkGoogle Scholar19. Scheffer PG, Teerlink T, Dekker JM, Bos G, Nijpels G, Diamant M, Kostense PJ, Stehouwer CD, Heine RJ. Increased plasma apolipoprotein C-III concentration independently predicts cardiovascular mortality: the Hoorn Study.Clin Chem. 2008; 54:1325–1330. doi: 10.1373/clinchem.2008.103234.CrossrefMedlineGoogle Scholar20. Wyler von Ballmoos MC, Haring B, Sacks FM. The risk of cardiovascular events with increased apolipoprotein CIII: A systematic review and meta-analysis.J Clin Lipidol. 2015; 9:498–510. doi: 10.1016/j.jacl.2015.05.002.CrossrefMedlineGoogle Scholar21. Zheng C, Azcutia V, Aikawa E, Figueiredo JL, Croce K, Sonoki H, Sacks FM, Luscinskas FW, Aikawa M. Statins suppress apolipoprotein CIII-induced vascular endothelial cell activation and monocyte adhesion.Eur Heart J. 2013; 34:615–624. doi: 10.1093/eurheartj/ehs271.CrossrefMedlineGoogle Scholar22. Bhatt DL, Steg PG, Brinton EA, Jacobson TA, Miller M, Tardif JC, Ketchum SB, Doyle RT, Murphy SA, Soni PN, Braeckman RA, Juliano RA, Ballantyne CM; REDUCE-IT Investigators. Rationale and design of REDUCE-IT: Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial.Clin Cardiol. 2017; 40:138–148. doi: 10.1002/clc.22692.CrossrefMedlineGoogle Scholar23. https://clinicaltrials.gov/ct2/show/NCT02104817. Accessed May 4, 2017.Google Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Adiels M, Taskinen M, Björnson E, Andersson L, Matikainen N, Söderlund S, Kahri J, Hakkarainen A, Lundbom N, Sihlbom C, Thorsell A, Zhou H, Pietiläinen K, Packard C and Borén J (2019) Role of apolipoprotein C‐III overproduction in diabetic dyslipidaemia, Diabetes, Obesity and Metabolism, 10.1111/dom.13744, 21:8, (1861-1870), Online publication date: 1-Aug-2019. Rivas-Urbina A, Rull A, Ordóñez-Llanos J and Sánchez-Quesada J Electronegative LDL: An Active Player in Atherogenesis or a By- Product of Atherosclerosis?, Current Medicinal Chemistry, 10.2174/0929867325666180330093953, 26:9, (1665-1679) Miller M (2018) Low-Density Lipoprotein Triglycerides, Journal of the American College of Cardiology, 10.1016/j.jacc.2018.03.541, 72:2, (170-172), Online publication date: 1-Jul-2018. Ramasamy I (2018) Update on the laboratory investigation of dyslipidemias, Clinica Chimica Acta, 10.1016/j.cca.2018.01.015, 479, (103-125), Online publication date: 1-Apr-2018. Colom C, Viladés D, Pérez-Cuellar M, Leta R, Rivas-Urbina A, Carreras G, Ordóñez-Llanos J, Pérez A and Sánchez-Quesada J (2018) Associations between epicardial adipose tissue, subclinical atherosclerosis and high-density lipoprotein composition in type 1 diabetes, Cardiovascular Diabetology, 10.1186/s12933-018-0794-9, 17:1, Online publication date: 1-Dec-2018. Thiriet M (2018) Hyperlipidemias and Obesity Vasculopathies, 10.1007/978-3-319-89315-0_5, (331-548), . June 2017Vol 37, Issue 6 Advertisement Article InformationMetrics © 2017 American Heart Association, Inc.https://doi.org/10.1161/ATVBAHA.117.309493PMID: 28539488 Originally publishedJune 1, 2017 Keywordscoronary artery diseaseEditorialshypertriglyceridemiaapolipoprotein C-IIIlipoproteins, VLDLlipoprotein lipasePDF download Advertisement
Referência(s)