title: Liver-specific transgenic expression of cholesteryl ester hydrolase reduces atherosclerosis in Ldlr-/- mice.
abstract: The liver plays a central role in the final elimination of cholesterol from the body either as bile acids or as free cholesterol (FC), and lipoprotein-derived cholesterol is the major source of total biliary cholesterol. HDL is the major lipoprotein responsible for removal and transport of cholesterol, mainly as cholesteryl esters (CEs), from the peripheral tissues to the liver. While HDL-FC is rapidly secreted into bile, the fate of HDL-CE remains unclear. We have earlier demonstrated the role of human CE hydrolase (CEH, CES1) in hepatic hydrolysis of HDL-CE and increasing bile acid synthesis, a process dependent on scavenger receptor BI expression. In the present study, we examined the hypothesis that by enhancing the elimination of HDL-CE into bile/feces, liver-specific transgenic expression of CEH will be anti-atherogenic. Increased CEH expression in the liver significantly increased the flux of HDL-CE to bile acids. In the LDLR(-/-) background, this enhanced elimination of cholesterol led to attenuation of diet-induced atherosclerosis with a consistent increase in fecal sterol secretion primarily as bile acids. Taken together with the observed reduction in atherosclerosis by increasing macrophage CEH-mediated cholesterol efflux, these studies establish CEH as an important regulator in enhancing cholesterol elimination and also as an anti-atherogenic target.
authors.affiliation: Department of Internal Medicine, Virginia Commonweath University Medical Center, Richmond, VA.
authors.forename: Jinghua
authors.initials: J
authors.lastname: Bie
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.forename: Quan
authors.initials: Q
authors.lastname: Yuan
authors.forename: Genta
authors.initials: G
authors.lastname: Kakiyama
authors.forename: Siddhartha S
authors.initials: SS
authors.lastname: Ghosh
authors.forename: Shobha
authors.initials: S
authors.lastname: Ghosh
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000097:blood / Q000201:enzymology*; D001647:Bile Acids and Salts / Q000378:metabolism; D002784:Cholesterol / Q000097:blood; D005260:Female; D015870:Gene Expression; D018149:Glucose Intolerance; D006801:Humans; D008099:Liver / Q000201:enzymology*; D008264:Macrophages / Q000201:enzymology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009928:Organ Specificity; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism; D002787:Sterol Esterase / Q000096:biosynthesis / Q000235:genetics*; D019076:Transgenes; D014280:Triglycerides / Q000378:metabolism
chemical_list: D001647:Bile Acids and Salts; D011973:Receptors, LDL; D014280:Triglycerides; D002784:Cholesterol; D002787:Sterol Esterase
keywords: bile acid excretion; cholesterol elimination; fecal bile acids; high density lipoprotein-cholesteryl ester hydrolysis; low density lipoprotein receptor