Hepatic over-expression of cholesteryl ester hydrolase enhances cholesterol elimination and in vivo reverse cholesterol transport

Bin Zhao, Jingmei Song, and Shobha Ghosh

Internal Medicine, Virginia Commonwealth University, Richmond, VA 23298-0050

Corresponding Author: shobha{at}vcu.edu

Neutral Cholesteryl ester hydrolase (CEH) mediated hydrolysis of cellular cholesteryl esters (CE) is required not only to generate free cholesterol 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 will regulate the hydrolysis of lipoprotein derived CE and enhance reverse cholesterol transport (RCT). Adenoviral mediated CEH over-expression 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 appearance of [3H]-cholesterol in gall bladder bile and feces over 48 hours was quantified. Mice over-expressing 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.

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