Carboxyl Ester Lipase Affects Hepatic HDL Metabolism

羧基酯脂肪酶影响肝脏 HDL 代谢

• 批准号: 7921129
• 负责人: PHILIP N HOWLES
• 金额: $ 7.76万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7921129
• 关键词: Affect; Animal Model; Bile Acid Biosynthesis Pathway; Bile Acids; Bile fluid; Biliary; Blood Circulation; Breeding; Cardiovascular Diseases; Cholesterol; Cholesterol Esters; Cholesterol Homeostasis; Communities; Complex; Cultured Cells; Data; Defect; Disease; Enzymes; Esters; Excision; Excretory function; Gender; Gene Expression; Gene Proteins; Goals; Hepatic; Hepatocyte; High Density Lipoprotein Cholesterol; High Density Lipoproteins; Hydrolysis; Knockout Mice; Lipase; Lipids; Lipoproteins; Liver; Mediating; Medical; Metabolic; Metabolism; Modeling; Morbidity - disease rate; Movement; Mus; Particle Size; Pathway interactions; Peripheral; Physiological; Play; Process; Proteins; Public Health; Research; Research Personnel; Risk; Role; Scientist; Serum; Societies; Sterols; Testing; Tissues; Transgenes; Transgenic Mice; Transgenic Organisms; Triglycerides; Work; base; bile salt-stimulated lipase; hypercholesterolemia; insight; lipoprotein triglyceride; liver function; mortality; particle; prevent; programs; research study; response; reverse cholesterol transport; scavenger receptor; sterol esterase; transcription factor; uptake

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：反向胆固醇转运（RCT）是多余的胆固醇从外周组织到肝脏的运动，以便将其作为胆固醇和胆汁酸。近年来，许多研究集中在寻找加强这一过程的方法，以预防和治疗心血管疾病。高密度脂蛋白（HDL）是RCT的主要车辆，主要作为胆固醇作为胆固醇酯。该提案的总体目标是更好地了解肝细胞从HDL中选择性去除并水解胆固醇酯的机制，并将自由胆固醇传递给胆汁或首先将其代谢为胆汁酸。特别是研究负责水解这些胆固醇酯的酶，以及如果不发生这种水解，则随之而来的代谢变化。肝酯脂肪酶（CEL），也称为胆固醇酯酶和胆汁盐刺激的脂肪酶，由肝脏制成并分泌。培养细胞和Cel-Null小鼠的初步结果表明，该酶在选择性摄取和随后的HDL胆固醇酯的水解中都起作用。提出了三个具体目标。 1）表征缺乏CEL的生理后果，并研究CEL影响肝胆固醇代谢的机制。胆固醇和胆汁酸合成以及脂蛋白代谢将在Cel-Null小鼠中研究。 2）检验以下假设：增加肝CEL表达将使用具有CEL肝脏表达升高的转基因小鼠增加选择性摄取和HDL胆固醇向胆汁的递送。 3）检验以下假设：从小鼠中取出CET表达CETP（胆固醇酯：甘油三酸酯转移蛋白）将增加HDL和富含甘油三酸酯的脂蛋白之间的脂质交换，并导致后者从循环中更快地去除。 CETP基因将通过与表达Simian CETP转基因的小鼠交叉杂交转移到Cel-Null小鼠中。与公共卫生的相关性：拟议的实验的结果将提供有关HDL功能和肝胆固醇代谢的有价值的信息，这些信息可能有助于确定增加胆固醇分解和排泄的新药理目标，从而降低心血管疾病的风险和进展。