Abstract 32: Liver-Specific Transgenic Expression of Cholesteryl Ester Hydrolase Reduces Atherosclerosis in LDLR-/- Mice
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 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 (CE) 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 cholesteryl ester hydrolase (CEH, CES1) in hepatic hydrolysis of HDL-CE and increasing bile acid synthesis, a process dependent on SR-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 led to significant increase in flux of HDL-CE to bile acids. In LDLR-/- background, this enhanced elimination of cholesterol led to attenuation of diet-induced atherosclerosis in LDLR-/-LCEH2 mice (Figure) 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.
Author Disclosures: J. Bie: None. J. Wang: None. Q. Yuan: None. G. Kakiyama: None. S.S. Ghosh: None. S. Ghosh: None.
- © 2014 by American Heart Association, Inc.