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Journal of Lipid Research, Vol. 48, 1476-1487, July 2007
Copyright © 2007 by American Society for Biochemistry and Molecular Biology

Effects of apoA-V on HDL and VLDL metabolism in APOC3 transgenic mice¹

Shen Qu^*, German Perdomo^*, Dongming Su^*, Fiona M. D'Souza^*, Neil S. Shachter and H. Henry Dong^2,*

^* Rangos Research Center, Children's Hospital of Pittsburgh, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213
Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY 10032

¹ This study was presented at the 66th American Diabetes Association Scientific Session, Washington, DC, June 9–13, 2006.

Published, JLR Papers in Press, April 16, 2007.

² To whom correspondence should be addressed. e-mail: dongh{at}pitt.edu

Apolipoprotein A-V (apoA-V) and apoC-III are exchangeable constituents of VLDL and HDL. ApoA-V counteracts the effect of apoC-III on triglyceride (TG) metabolism with poorly defined mechanisms. To better understand the effects of apoA-V on TG 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 TG levels were reduced significantly as a result of enhanced VLDL catabolism without alternations in VLDL production. This effect was associated with reduced apoC-III content in VLDL. Increased 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 -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, increased apoA-V levels accounted for cholesterol redistribution from VLDL to larger HDL particles. These data suggest that in addition to its TG-lowering effect, apoA-V plays a significant role in modulating HDL maturation and cholesterol metabolism.

Supplementary key words apolipoprotein A-V • apolipoprotein C-III • hypertriglyceridemia • lipoprotein metabolism • very low density lipoprotein • high density lipoprotein

Abbreviations: apoA-V, apolipoprotein A-V; LDLR, low density lipoprotein receptor; SR-BI, scavenger receptor class B type I; TG, triglyceride

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