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

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

Nature Medicine 23. (21 August 2017): 1086-1094. 

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) levels¹. 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 clearance². Here we report a detailed interrogation of the mechanism of TRL lowering by the APOC3Ala43Thr (A43T) variant, the only missense (rather than protein-truncating) variant in APOC3reported to be TG lowering and protective against CHD^{3, 4, 5}. We found that both human APOC3A43T 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.