title: Liver-specific cholesteryl ester hydrolase deficiency attenuates sterol elimination in the feces and increases atherosclerosis in ldlr-/- mice.
abstract: OBJECTIVE
  Liver is the major organ responsible for the final elimination of cholesterol from the body either as biliary cholesterol or as bile acids. Intracellular hydrolysis of lipoprotein-derived cholesteryl esters (CEs) is essential to generate the free cholesterol required for this process. Earlier, we demonstrated that overexpression of human CE hydrolase (Gene symbol CES1) increased bile acid synthesis in human hepatocytes and enhanced reverse cholesterol transport in mice. The objective of the present study was to demonstrate that liver-specific deletion of its murine ortholog, Ces3, would decrease cholesterol elimination from the body and increase atherosclerosis.
  
  
  RESULTS
  Liver-specific Ces3 knockout mice (Ces3-LKO) were generated, and Ces3 deficiency did not affect the expression of genes involved in cholesterol homeostasis and free cholesterol or bile acid transport. The effects of Ces3 deficiency on the development of Western diet-induced atherosclerosis were examined in low density lipoprotein receptor knock out(-/-) mice. Despite similar plasma lipoprotein profiles, there was increased lesion development in low density lipoprotein receptor knock out(-/-)Ces3-LKO mice along with a significant decrease in the bile acid content of bile. Ces3 deficiency significantly reduced the flux of cholesterol from [(3)H]-CE-labeled high-density lipoproteins to feces (as free cholesterol and bile acids) and decreased total fecal sterol elimination.
  
  
  CONCLUSIONS
  Our results demonstrate that hepatic Ces3 modulates the hydrolysis of lipoprotein-delivered CEs and thereby regulates free cholesterol and bile acid secretion into the feces. Therefore, its deficiency results in reduced cholesterol elimination from the body, leading to significant increase in atherosclerosis. Collectively, these data establish the antiatherogenic role of hepatic CE hydrolysis.
authors.affiliation: Department of Internal Medicine, VCU Medical Center, Richmond, VA 23298-0050, USA.
authors.forename: Jinghua
authors.initials: J
authors.lastname: Bie
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Marqueen
authors.forename: Rachel
authors.initials: R
authors.lastname: Osborne
authors.forename: Genta
authors.initials: G
authors.lastname: Kakiyama
authors.forename: William
authors.initials: W
authors.lastname: Korzun
authors.forename: Siddhartha S
authors.initials: SS
authors.lastname: Ghosh
authors.forename: Shobha
authors.initials: S
authors.lastname: Ghosh
mesh_terms: D000821:Animal Feed; D000818:Animals; D050197:Atherosclerosis / Q000235:genetics* / Q000378:metabolism*; D001647:Bile Acids and Salts / Q000378:metabolism; D002265:Carboxylic Ester Hydrolases / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D015243:Cholesterol, VLDL / Q000097:blood; D005243:Feces / Q000201:enzymology; D005260:Female; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D008099:Liver / Q000201:enzymology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018110:Receptors, Lipoprotein / Q000235:genetics* / Q000378:metabolism; D013261:Sterols / Q000378:metabolism*
chemical_list: D001647:Bile Acids and Salts; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D015243:Cholesterol, VLDL; C050009:IDL receptor; D018110:Receptors, Lipoprotein; D013261:Sterols; D002265:Carboxylic Ester Hydrolases; C545375:carboxylesterase 1, mouse
keywords: and salts; atherosclerosis; bile acids; cholesterol; cholesteryl ester hydrolysis; knockout mice