Effects of apoA-V on HDL and VLDL metabolism in APOC3 transgenic mice

Shen Qu, German Perdomo, Dongming Su, Fiona M. D'Souza, Neil S. Shachter, and H. Henry Dong

Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213

Corresponding Author: dongh{at}pitt.edu

Apolipoproteins A-V and C-III are exchangeable constituents of VLDL and HDL. ApoA-V counteracts the effect of apoC-III on triglyceride metabolism with poorly defined mechanisms. To better understand the effects of apoA-V on triglyceride and cholesterol metabolism, we delivered apoA-V cDNA into livers of hypertriglyceridemic APOC3 transgenic mice by adenovirus-mediated gene transfer. In response to hepatic apoA-V production, plasma triglyceride levels was significantly reduced, due to enhanced VLDL catabolism without alternations in VLDL production. This effect was associated with reduced apoC-III content in VLDL. Elevated apoA-V production also resulted in decreased apoC-III and increased apoA-I content in HDL. Furthermore, ApoA-V-enriched HDL was associated with enhanced LCAT activity and increased cholesterol efflux. This effect, along with apoE enrichment in HDL, contributed to HDL core expansion and alpha-HDL formation, accounting for significant increases in both the number and size of HDL particles. As a result, apoA-V-treated APOC3 transgenic mice exhibited decreased VLDL-cholesterol and increased HDL-cholesterol levels. ApoA-V-mediated reduction of apoC-III content in VLDL represents an important mechanism by which apoA-V acts to ameliorate hypertriglyceridemia in adult APOC3 transgenic mice. In addition, elevated apoA-V levels accounted for cholesterol redistribution from VLDL to larger-sized HDL particles. These data suggest that in addition to its triglyceride-lowering effect, apoA-V plays a significant role in modulating HDL maturation and cholesterol metabolism.

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