DIET, HDL, AND REVERSE CHOLESTEROL TRANSPORT

饮食、高密度脂蛋白和胆固醇反向运输

• 批准号: 6389020
• 负责人: DAVID K SPADY
• 金额: $ 25.01万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-04-01 至 2004-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6389020
• 关键词: blood lipoprotein metabolism; blood lipoprotein transport; cholanate compound; cholesterol; cholesterol esters; dietary constituent; dietary lipid; enzyme activity; excretion; gene expression; genetically modified animals; hamsters; high density lipoproteins; laboratory mouse; lipid transport; liver metabolism; low density lipoprotein; nutrient interaction; nutrition related tag; phosphatidylcholine sterol acyltransferase; receptor expression; steroid biosynthesis; transport proteins

Cholesterol that is acquired by most extrahepatic tissues must be returned to the liver for excretion in a process that has been termed reverse cholesterol transport. The concept of reverse cholesterol transport is based mainly on biochemical studies of individual enzymes thought to be involved in reverse cholesterol transport and studies of cholesterol efflux from cultured cells. More recently, proteins thought to be involved in reverse cholesterol transport have been knocked out or overexpressed in mice. However, there is no direct evidence that reverse cholesterol transport has been altered in any of these models. To date, an unambiguous demonstration of the reverse cholesterol transport pathway has not been obtained in whole animals. In preliminary studies we demonstrated the net (mass) movement of cholesterol from individual extrahepatic tissues into reconstituted nascent prebeta-migrating HDL in vivo and showed that this initial step in reverse cholesterol transport can be greatly accelerated. Here we propose to characterize the major steps in reverse cholesterol transport in vivo and to demonstrate sequentially that each step in the reverse cholesterol transport pathway can be accelerated resulting in the net (mass) movement of cholesterol from extrahepatic tissues to the liver for excretion into bile. Finally, we will demonstrate that cholesterol flux through the entire reverse cholesterol transport pathway can be accelerated in vivo resulting in the net movement of cholesterol from individual extrahepatic tissues into feces. These goals are now feasible because of methodological advances that allow us to quantify, for the first time, the major pathways of sterol flux in all tissues of the body in vivo. The specific aims are: (1) to characterize the initial step in the reverse cholesterol transport pathway in vivo in terms of the effect of enhanced cholesterol efflux on pathways of cholesterol acquisition by extrahepatic tissues, the effect of acceptor particle composition on cholesterol efflux and the effect of diet on cholesterol efflux, (2) to characterize the effects of overexpressing lecithin cholesterol acyl transferase (LCAT) on reverse cholesterol transport in vivo, (3) To determine the metabolic consequences of increasing the flux of HDL cholesteryl ester or LDL cholesterol to the liver and (4) to demonstrate that cholesterol flux through the entire reverse cholesterol transport pathway can be accelerated in vivo resulting in the net movement of cholesterol from extrahepatic tissues into feces both in animals that lack and in animals that possess cholesteryl ester transfer protein (CETP).

大多数肝外组织获得的胆固醇必须返回肝脏排泄，这一过程被称为逆向胆固醇运输。胆固醇逆向转运的概念主要是基于对被认为参与胆固醇逆向转运的单个酶的生化研究和对培养细胞中胆固醇外排的研究。最近，一些被认为参与逆向胆固醇运输的蛋白质在小鼠体内被敲除或过度表达。然而，没有直接证据表明，在这些模型中，逆向胆固醇转运已经改变。迄今为止，尚未在全动物中获得胆固醇逆向转运途径的明确证明。在初步研究中，我们证明了胆固醇在体内从单个肝外组织向新生β -迁移前HDL的净（质量）移动，并表明这一逆向胆固醇运输的初始步骤可以大大加速。在这里，我们建议描述体内胆固醇逆向运输的主要步骤，并依次证明胆固醇逆向运输途径中的每个步骤都可以加速，从而导致胆固醇从肝外组织净（大量）移动到肝脏并排泄到胆汁中。最后，我们将证明通过整个胆固醇逆向运输途径的胆固醇通量在体内可以加速，从而导致胆固醇从个体肝外组织净移动到粪便中。这些目标现在是可行的，因为方法上的进步使我们第一次能够量化体内所有组织中固醇通量的主要途径。具体目标是：(1)从胆固醇外排增强对肝外组织胆固醇获取途径的影响、受体颗粒组成对胆固醇外排的影响以及饮食对胆固醇外排的影响等方面，表征体内胆固醇逆向转运途径的初始阶段；(2)表征过表达卵磷脂胆固醇酰基转移酶（LCAT）对体内胆固醇逆向转运的影响；(3)确定增加高密度脂蛋白胆固醇酯或低密度脂蛋白胆固醇到肝脏的通量的代谢后果；(4)证明胆固醇通过整个逆向胆固醇运输途径的通量在体内可以加速，导致胆固醇在缺乏和拥有胆固醇酯转移蛋白（CETP）的动物中从肝外组织进入粪便的净运动。