Abstract 11275: Liver-specific Ces3 Deficiency Attenuates High-Fat High-Cholesterol Diet Induced Atherosclerosis in LDLR-/- Mice

Abstract

Liver is the major organ responsible for the final elimination of cholesterol from the body either as biliary cholesterol or bile acids. Intracellular hydrolysis of lipoprotein-derived cholesteryl esters (CE) is essential to generate the free cholesterol (FC) required for this process. We have earlier identified and characterized cholesteryl ester hydrolase (CEH, gene symbol CES1) from human liver and demonstrated its role in increasing bile acid synthesis and thereby enhancing macrophage-to-feces reverse cholesterol transport. We hypothesized that liver-specific deletion of its murine ortholog, Ces3, would decrease cholesterol elimination from the body and would, therefore, be atherogenic. Liver-specific Ces3 knockout mice (Ces3-LKO) were generated by crossing Ces3 floxed mice with Alb-Cre transgenic mice. Consistent with a loss of hepatic Ces3, there was a significant increase in hepatic CE levels in Ces3 knockout mice fed a Western diet and a significant decrease in removal of HDL-CE into feces, either as FC or bile acids. To evaluate the effects of hepatic Ces3 deficiency on the development of atherosclerosis, Ces3-LKO mice were crossed into LDLR-/- background and littermates (LDLR-/- and LDLR-/-Ces3-LKO) were fed a Western diet (TD88137) for 16 weeks. Development of diet-induced atherosclerosis was assessed by en face analyses and by measuring aortic cholesterol content. Despite similar plasma lipoprotein profiles, there was significantly increased lesion development in LDLR-/-Ces3-LKO mice compared to LDLR-/-, representative image shown in the Figure (Panel A). Consistently, there was an increase in the cholesterol content of the aorta (Panel B). These data demonstrate that hepatic Ces3 modulates hydrolysis of HDL-CE and thereby regulates FC as well as bile acid secretion into the feces. Its deficiency, therefore, results in significant increase in diet-induced atherosclerosis establishing the anti-atherogenic role of hepatic CE hydrolysis.