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Journal of Lipid Research, Vol. 49, 2212-2217, October 2008 Hepatic overexpression of cholesteryl ester hydrolase enhances cholesterol elimination and in vivo reverse cholesterol transport
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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