A human APOC3 missense variant and monoclonal antibody accelerate apoC-III clearance and lower triglyceride-rich lipoprotein levels

作者：Khetarpal Sumeet A; Zeng Xuemei; Millar John S; Vitali Cecilia; Somasundara Amritha Varshini Hanasoge; Zanoni Paolo; Landro James A; Barucci Nicole; Zavadoski William J; Sun Zhiyuan; de Haard Hans; Toth Ildiko V; Peloso Gina M; Natarajan Pradeep; Cuchel Marina; Lund Katz Sissel; Phillips Michael C; Tall Alan R; Kathiresan Sekar; DaSilva Jardine Paul; Yates Nathan A; Rader Daniel J

来源：Nature Medicine, 2017, 23(9): 1086-+.

DOI：10.1038/nm.4390

Recent large-scale genetic sequencing efforts have identified rare coding variants in genes in the triglyceride-rich lipoprotein (TRL) clearance pathway that are protective against coronary heart disease (CHD), independently of LDL cholesterol (LDL-C) levels(1). Insight into the mechanisms of protection of these variants may facilitate the development of new therapies for lowering TRL levels. The gene APOC3 encodes apoC-III, a critical inhibitor of triglyceride (TG) lipolysis and remnant TRL clearance(2). Here we report a detailed interrogation of the mechanism of TRL lowering by the APOC3 Ala43Thr (A43T) variant, the only missense (rather than protein-truncating) variant in APOC3 reported to be TG lowering and protective against CHD3-5. We found that both human APOC3 A43T heterozygotes and mice expressing human APOC3 A43T display markedly reduced circulating apoC-III levels. In mice, this reduction is due to impaired binding of A43T apoC-III to lipoproteins and accelerated renal catabolism of free apoC-III. Moreover, the reduced content of apoC-III in TRLs resulted in accelerated clearance of circulating TRLs. On the basis of this protective mechanism, we developed a monoclonal antibody targeting lipoprotein-bound human apoC-III that promotes circulating apoC-III clearance in mice expressing human APOC3 and enhances TRL catabolism in vivo. These data reveal the molecular mechanism by which a missense variant in APOC3 causes reduced circulating TG levels and, hence, protects from CHD. This protective mechanism has the potential to be exploited as a new therapeutic approach to reduce apoC-III levels and circulating TRL burden.

• 出版日期2017-9