Abstract 5476: Hepatic Over-Expression of Cholesteryl Ester Hydrolase Enhances Cholesterol Elimination and in vivo Reverse Cholesterol Transport

Abstract

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 (>3 fold) in bile acid output (see Figure ). To assess the role of hepatic CEH in promoting flux of cholesterol from macrophages to feces, cholesterol loaded and [ 3 H]-cholesterol labeled J774 macrophages were injected intraperitoneally into mice and appearance of [ 3 H]-cholesterol in gall bladder bile and feces over 48 hours was quantified. Mice over-expressing CEH had significantly higher [ 3 H]-cholesterol in bile and feces and it was associated with bile acids. This CEH-mediated increased movement of [ 3 H]-cholesterol from macrophages to bile 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. This research has received full or partial funding support from the American Heart Association, AHA Mid-Atlantic Affiliate (Maryland, North Carolina, South Carolina, Virginia & Washington, DC).