Immunochemical Structure/Function of Apolipoprotein A-I

载脂蛋白 A-I 的免疫化学结构/功能

基本信息

批准号：
7258356
负责人：
Linda K Curtiss
金额：
$ 44.07万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
1990
资助国家：
美国
起止时间：
1990-07-01 至 2009-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7258356
关键词：
Aorta Apolipoprotein A-I Apolipoprotein E Apoproteins Arterial Fatty Streak Atherosclerosis Bile Acids Biliary Binding Cells Cholesterol Cholesterol Ester Transfer Proteins Data Event Excretory function Extracellular Space Foam Cells Generations Grant High Density Lipoproteins Hydrolase Hydrolysis In Vitro Intervention Lesion Ligation Lipase Lipids Lipoprotein (a)Lipoprotein (a-)Liver Low Density Lipoprotein Receptor Mediating Movement Mus Nuclear Particle Size Pathway interactions Peripheral Persons Phospholipid Transfer Proteins Phospholipids Plasma Process Property Proteins Publishing Rate Risk Role Role playing therapy Specificity Structure Testing Tissues Triglycerides feeding hepatic lipase human CETP protein in vivo lipid transfer protein lipoprotein lipase lipoprotein triglyceride macrophage phospholipid exchange proteins receptor reverse cholesterol transport

项目摘要

DESCRIPTION (provided by applicant): Low levels of high density lipoprotein (HDL) are a powerful predictor for identifying persons who are at risk for atherosclerosis. Moreover HDL is an important target for pharmacologic intervention to reduce this risk. This grant will focus on the cellular efflux properties of the major protein of HDL, apolipoprotein AI (apoAI). Plasma HDL levels do not control the rate of cellular cholesterol efflux. Instead, efflux occurs in extracellular spaces. 2 events dictate the rate of movement of cholesterol out of peripheral cells: an energy-dependent transport of cholesterol out of the cell, a process carried out by ABCA1; and the availability of a lipid-poor acceptor of this transported cholesterol, an amphipathic alpha helical apoprotein. Studies in vitro have verified that many apoproteins including apoproteins AI, All, AIV and E are equally good acceptors of cellular cholesterol. Only apoAI will mediate macrophage (Mphi)-mediated lipid efflux from foam cells within atherosclerotic lesions. This proposal will test the hypothesis that this in vivo specificity for apoAI is a function of the ability of apoAI to dissociate from spherical alpha-migrating HDL and form transiently stable, lipid-poor apoAI. Our studies are performed in low density lipoprotein receptor-deficient (LDLr-/-) mice and involve 3 specific aims. The first aim will identify the role of phospholipid transfer protein (PLTP) in the generation of lipid-poor apoAI in vivo and in vitro. The second aim will identify the role played by cholesterol ester transfer protein (CETP) in this same process. Both of these transfer proteins are expressed in Mphi, can generate lipid-poor apoAI from spherical HDL and are induced by ligation of nuclear liver X receptors (LXR). The third aim will identify the role of lipoprotein lipase (LpL) and hepatic lipase (HL) in the generation of lipid-poor apo AI. These lipases also are expressed by Mphi and regulated by LXR. We propose that core lipid reduction by triglyceride hydrolysis and remodeling by PLTP and CETP release lipid-poor apoAI from HDL to facilitate efflux from Mphi foam cells within atherosclerotic lesions.

描述（由申请人提供）：低水平的高密度脂蛋白（HDL）是识别有动脉粥样硬化风险的人的有力预测因子。此外，HDL 是降低这种风险的药物干预的重要目标。这笔资助将重点研究 HDL 主要蛋白载脂蛋白 AI (apoAI) 的细胞流出特性。血浆高密度脂蛋白水平不控制细胞胆固醇流出的速率。相反，外排发生在细胞外空间。 2 个事件决定了胆固醇从外周细胞中移出的速率：胆固醇从细胞中的能量依赖性转运，该过程由 ABCA1 执行；以及这种转运胆固醇的贫脂受体（一种两亲性α螺旋脱辅基蛋白）的可用性。体外研究已经证实，许多脱辅基蛋白，包括脱辅基蛋白AI、All、AIV和E，都是同样良好的细胞胆固醇受体。只有 apoAI 能够介导巨噬细胞 (Mphi) 介导的脂质从动脉粥样硬化病变内的泡沫细胞流出。该提案将检验以下假设：apoAI 的体内特异性是 apoAI 从球形 α 迁移 HDL 解离并形成瞬时稳定、缺乏脂质的 apoAI 的能力的函数。我们的研究是在低密度脂蛋白受体缺陷 (LDLr-/-) 小鼠中进行的，涉及 3 个具体目标。第一个目标是确定磷脂转移蛋白 (PLTP) 在体内和体外生成贫脂 apoAI 中的作用。第二个目标是确定胆固醇酯转移蛋白（CETP）在同一过程中所发挥的作用。这两种转移蛋白均在 Mphi 中表达，可以从球形 HDL 生成贫脂 apoAI，并由核肝 X 受体 (LXR) 连接诱导。第三个目标是确定脂蛋白脂肪酶 (LpL) 和肝脂肪酶 (HL) 在产生贫脂 apo AI 中的作用。这些脂肪酶也由 Mphi 表达并受 LXR 调节。我们提出，通过甘油三酯水解降低核心脂质，并通过 PLTP 和 CETP 重塑，从 HDL 中释放脂质贫乏的 apoAI，以促进动脉粥样硬化病变内 Mphi 泡沫细胞的流出。