Exploring apolipoprotein C-III: pathophysiological and pharmacological relevance.

The availability of pharmacological approaches able to effectively reduce circulating LDL cholesterol (LDL-C) has led to a substantial reduction in the risk of atherosclerosis-related cardiovascular disease (CVD). However, a residual cardiovascular (CV) risk persists in treated individuals with optimal levels of LDL-C. Additional risk factors beyond LDL-C are involved, and among these, elevated levels of triglycerides (TGs) and TG-rich lipoproteins are causally associated with an increased CV risk. Apolipoprotein C-III (apoC-III) is a key regulator of TG metabolism and hence circulating levels through several mechanisms including the inhibition of lipoprotein lipase activity and alterations in the affinity of apoC-III-containing lipoproteins for both the hepatic receptors involved in their removal and extracellular matrix in the arterial wall. Genetic studies have clarified the role of apoC-III in humans, establishing a causal link with CVD and showing that loss-of-function mutations in the APOC3 gene are associated with reduced TG levels and reduced risk of coronary heart disease. Currently available hypolipidaemic drugs can reduce TG levels, although to a limited extent. Substantial reductions in TG levels can be obtained with new drugs that target specifically apoC-III; these include two antisense oligonucleotides, one small interfering RNA and an antibody.

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Déclaration de conflit d'intérêts

Conflict of interest: C.J.P. reports grant funding/honoraria from Amarin, Amgen, Daiichi-Sankyo, SalCor, MSD, and Novartis. A.P. has nothing to disclose. S.T. is a co-inventor and receives royalties from patents owned by University of California San Diego (UCSD) and is a co-founder and has an equity interest in Oxitope, LLC, and its affiliates, Kleanthi Diagnostics, LLC, and Covicept Therapeutics, Inc., and has a dual appointment at UCSD and Ionis Pharmaceuticals. Although these relationships have been identified for conflict of interest management based on the overall scope of the project, the research findings included in this particular publication may not necessarily relate to the interests of the above companies. The terms of this arrangement have been reviewed and approved by the UCSD in accordance with its conflict of interest policies. B.A.F. reports research grants from Merck, Novartis, Amgen, and Esperion Therapeutics and consulting fees, advisory boards, or lecture honoraria from Novartis, Merck, Amgen, Regeneron, Sanofi, Novartis, Pfizer, Eli Lilly, Novo Nordisk, Daiichi-Sankyo, Viatris, Ionis Pharmaceuticals, New Amsterdam Pharmaceuticals, dalCOR, The Medicines Co, Mylan, CiVi Pharma, KrKa Phamaceuticals, American College of Cardiology, EAS, and European Society of Cardiology. A.L.C. reports grant(s)/support from Akcea, Amarin, Amgen, Menarini, Mylan, Sanofi, and Sanofi/Regeneron and is a consultant for Akcea, Amgen, Amarin, Daiichi-Sankyo, Eli Lilly, Esperion, Kowa, Ionis Pharmaceuticals, Menarini, MSD, Mylan, Novartis, Recordati, Regeneron, and Sanofi, outside the submitted work.