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Originally published In Press as doi:10.1194/jlr.M800277-JLR200 on July 3, 2008

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Journal of Lipid Research, Vol. 49, 2212-2217, October 2008
Copyright © 2008 by American Society for Biochemistry and Molecular Biology

Hepatic overexpression of cholesteryl ester hydrolase enhances cholesterol elimination and in vivo reverse cholesterol transport

Bin Zhao, Jingmei Song and Shobha Ghosh1

Department of Internal Medicine, Virginia Commonwealth University Medical Center, Richmond, VA 23298-0050

This work was supported by American Heart Association Grant 0755392U to S.G.

Published, JLR Papers in Press, July 3, 2008.

1 To whom correspondence should be addressed. e-mail: shobha{at}vcu.edu

Neutral cholesteryl ester hydrolase (CEH)-mediated hydrolysis of cellular cholesteryl esters (CEs) is required not only to generate free cholesterol (FC) for efflux from macrophages but also to release FC from lipoprotein-delivered CE in the liver for bile acid synthesis or direct secretion into the bile. We hypothesized that hepatic expression of CEH would regulate the hydrolysis of lipoprotein-derived CE and enhance reverse cholesterol transport (RCT). Adenoviral-mediated CEH overexpression led to a significant increase in bile acid output. To assess the role of hepatic CEH in promoting flux of cholesterol from macrophages to feces, cholesterol-loaded and [3H]cholesterol-labeled J774 macrophages were injected intraperitoneally into mice and the appearance of [3H]cholesterol in gallbladder bile and feces over 48 h was quantified. Mice overexpressing CEH had significantly higher [3H]cholesterol radiolabel in bile and feces, and it was associated with bile acids. This CEH-mediated increased movement of [3H]cholesterol from macrophages to bile acids and feces was significantly attenuated in SR-BI–/– mice. These studies demonstrate that similar to macrophage CEH that rate-limits the first step, hepatic CEH regulates the last step of RCT by promoting the flux of cholesterol entering the liver via SR-BI and increasing hepatic bile acid output.

Supplementary key words liver • bile acid excretion • lipoprotein cholesterol removal • selective uptake • HDL cholesteryl esters


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