Hepatic overexpression of cholesteryl ester hydrolase enhances cholesterol elimination and in vivo reverse cholesterol transport.
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.
Zhao
Bin
B
Department of Internal Medicine, Virginia Commonwealth University Medical Center, Richmond, VA 23298-0050, USA.
Song
Jingmei
J
Ghosh
Shobha
S
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001646:Bile / Q000378:metabolism; D001647:Bile Acids and Salts / Q000378:metabolism; D001692:Biological Transport; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism*; D008076:Cholesterol, HDL / Q000378:metabolism; D005243:Feces; D015870:Gene Expression; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D008074:Lipoproteins / Q000097:blood; D008099:Liver / Q000201:enzymology / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D002787:Sterol Esterase / Q000235:genetics / Q000378:metabolism*
D001647:Bile Acids and Salts; D008076:Cholesterol, HDL; D008074:Lipoproteins; D002784:Cholesterol; D002787:Sterol Esterase