Carboxyl Ester Lipase Affects Hepatic HDL Metabolism
Principal Investigator: PHILIP HOWLES
Abstract: Reverse Cholesterol Transport (RCT) is the movement of excess cholesterol from peripheral tissues to the liver for disposal as biliary cholesterol and bile acids. In recent years, much research has focused on finding ways to enhance this process so as to both prevent and treat cardiovascular disease. High density lipoproteins (HDL) are the primary vehicles for RCT and transport the cholesterol primarily as cholesteryl esters. The overall goal of this proposal is to better understand the mechanisms by which hepatocytes selectively remove and hydrolyze cholesteryl esters from HDL and deliver the free cholesterol to bile or first metabolize it to bile acids. Particular focus is given to study of the enzyme(s) responsible for hydrolyzing these cholesteryl esters and the metabolic changes that ensue if this hydrolysis does not occur. Carboxyl ester lipase (CEL), also called cholesterol esterase and bile salt-stimulated lipase, is made and secreted by the liver. Preliminary results from cultured cells and CEL-null mice show that this enzyme plays a role in both the selective uptake and the subsequent hydrolysis of HDL cholesteryl esters. Three specific aims are proposed. 1) Characterize the physiological consequences of the absence of CEL and investigate the mechanism by which CEL affects hepatic cholesterol metabolism. Cholesterol and bile acid synthesis as well as lipoprotein metabolism will be studied in CEL-null mice. 2) Test the hypothesis that increasing hepatic CEL expression will increase selective uptake and delivery of HDL cholesterol to the bile using transgenic mice with elevated liver expression of CEL. 3) Test the hypothesis that removing CEL from mice that express CETP (cholesteryl ester:triglyceride transfer protein) will increase lipid exchange between HDL and triglyceride-rich lipoproteins and result in more rapid removal of the latter from the circulation. The CETP gene will be transferred to CEL-null mice by cross-breeding with mice that express a simian CETP transgene. Relevance to Public Health: The results of the proposed experiments will provide valuable information about HDL function and liver cholesterol metabolism that may help identify new pharmacologic targets for increasing cholesterol breakdown and excretion, thereby reducing the risk for and progression of cardiovascular disease.
Funding Period: 2006-08-01 - 2010-07-31
more information: NIH RePORT
- Reverse cholesterol transport is elevated in carboxyl ester lipase-knockout miceLisa M Camarota
Department of Pathology, Metabolic Diseases Institute, University of Cincinnati College of Medicine, Cincinnati, OH 45237, USA
FASEB J 25:1370-7. 2011..Together, the data demonstrate significantly increased RCT in the absence of CEL and suggest a novel mechanism by which to manipulate plasma cholesterol flux...
- Development and physiological regulation of intestinal lipid absorption. III. Intestinal transporters and cholesterol absorptionDavid Y Hui
Dept of Pathology and Laboratory Medicine, Genome Research Institute, Univ of Cincinnati College of Medicine, 2120 E Galbraith Rd, Cincinnati, OH 45237, USA
Am J Physiol Gastrointest Liver Physiol 294:G839-43. 2008..Another ATP transporter, ABCA1, is present in the basolateral membrane to mediate HDL secretion from enterocytes...
- Reduced absorption of saturated fatty acids and resistance to diet-induced obesity and diabetes by ezetimibe-treated and Npc1l1-/- miceEric D Labonté
Dept of Pathology, Genome Research Institute, Univ of Cincinnati, 2120 E Galbraith Rd, Cincinnati, OH 45237, USA
Am J Physiol Gastrointest Liver Physiol 295:G776-83. 2008..These unexpected beneficial results may be clinically important, given the focus on NPC1L1 as a target for the treatment of hypercholesterolemia...