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Originally published In Press as doi:10.1194/jlr.M600498-JLR200 on April 16, 2007

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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{dagger} and H. Henry Dong2,*

* Rangos Research Center, Children's Hospital of Pittsburgh, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213
{dagger} 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 {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, 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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