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

Nature Medicine 23, 1086 (2017). doi:10.1038/nm.4390 Authors: Sumeet A Khetarpal, Xuemei Zeng, John S Millar, Cecilia Vitali, Amritha Varshini Hanasoge Somasundara, Paolo Zanoni, James A Landro, Nicole Barucci, William J Zavadoski, Zhiyuan Sun, Hans de Haard, Ildikó V Toth, Gina M Peloso, Pradeep Natarajan, Marina Cuchel, Sissel Lund-Katz, Michael C Phillips, Alan R Tall, Sekar Kathiresan, Paul DaSilva-Jardine, Nathan A Yates & Daniel J Rader 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. 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. 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 CHD. 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...
Source: Nature Medicine - Category: General Medicine Authors: Tags: Letter Source Type: research