SR-BI MEDIATED SELECTIVE CHOLESTEROL ESTER UPTAKE

SR-BI 介导的选择性胆固醇酯摄取

基本信息

批准号：
6629853
负责人：
FREDERICK C. DE BEER
金额：
$ 22.05万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-03-01 至 2006-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6629853
关键词：
biotransformation cholesterol esters high density lipoproteins human tissue laboratory mouse lipid metabolism lipid transport phosphatidylcholine sterol acyltransferase protein metabolism protein structure receptor binding transfection /expression vector

项目摘要

DESCRIPTION: There is interest in understanding the factors that regulate HDL and apoA-I levels in humans as these are inversely correlated with the risk for atherosclerotic vascular disease. Plasma levels of HDL and apoA-I are related to the rate of apoA-I catabolism rather than apoA-I production. Neither the mechanisms underlying accelerated catabolism nor the site(s) of apoA-I removal from plasma have been clearly delineated. This proposal focuses on the role of the HDL receptor, SR-B1, in regulating apoA-I catabolic rate. SR-B1 delivers cholesteryl ester to cells via a process that is fundamentally distinct from receptor-mediated endocytosis. During this process, HDL binds to SR-B1 on the cell surface and transfers cholesteryl ester from the core of the particle to the cell without internalization of the apolipoprotein moiety. Despite the absence of apolipoprotein uptake, increased selective lipid uptake in the liver mediated by SR-B1 is associated with increased catabolism of apoA-I, and at least some of this catabolism occurs in the kidney. Thus, a central hypothesis of this proposal is that SR-B1 interaction with HDL initiates changes in the lipoprotein particle that promotes subsequent catabolism by a mechanism that is independent of SR-B1. SR-B1 binds with high affinity a number of different lipoprotein particles in addition to HDL, including VLDL, LDL, and oxidized LDL. The important metabolic event subsequent to lipoprotein binding by SR-B1 is the selective delivery of CE from the core of particles to cells. We propose that apoA-I is a critical ligand for SR-B1-mediated selective uptake, and that apoA-I conformation on the HDL particle can influence its interaction with SR-B1 to impede or promote receptor binding and/or selective uptake. The efficiency of selective uptake mediated by SR-B1:apoA-I interaction can be modulated by properties of the HDL particle (lipid composition, apolipoprotein content, or the structure of apoA-I itself). These hypotheses will be tested by defining: 1) the sub-population of HDL particles that are the preferred substrate for SR-B1-mediated lipid transfer; 2) the structure and composition of HDL particles after processing by SR-B1 (including the potential for apoA-I proteolysis); and 3) the metabolic fate of HDL particles after SR-B1 processing. Understanding the role of SR-B1 in HDL metabolism could define new areas for potential therapeutic assault.

描述：有兴趣了解调节 HDL 的因素和 apoA-I 水平在人类中的水平，因为这些与以下风险呈负相关：动脉粥样硬化性血管疾病。 HDL 和 apoA-I 的血浆水平相关与 apoA-I 分解代谢的速率有关，而不是与 apoA-I 的产生有关。既没有加速分解代谢的机制或 apoA-I 去除的位点血浆中的物质已被清楚地描绘出来。该提案的重点是 HDL 受体 SR-B1 调节 apoA-I 分解代谢率。 SR-B1 提供胆固醇酯进入细胞的过程与受体介导的内吞作用。在此过程中，HDL 与 SR-B1 结合细胞表面并将胆固醇酯从颗粒核心转移到没有载脂蛋白部分内化的细胞。尽管缺乏载脂蛋白摄取，肝脏选择性脂质摄取增加由 SR-B1 介导的 ApoA-I 分解代谢增加与这种分解代谢至少有一部分发生在肾脏中。因此，一个中心假设该提案的主要内容是 SR-B1 与 HDL 的相互作用引发了脂蛋白颗粒，通过以下机制促进随后的分解代谢：独立于SR-B1。 SR-B1 以高亲和力结合许多不同的除 HDL 之外的脂蛋白颗粒，包括 VLDL、LDL 和氧化脂蛋白颗粒低密度脂蛋白。 SR-B1 结合脂蛋白后的重要代谢事件是CE从颗粒核心选择性递送至细胞。我们建议 apoA-I 是 SR-B1 介导的选择性摄取的关键配体，并且 HDL 颗粒上的 apoA-I 构象可以影响其与 SR-B1 阻碍或促进受体结合和/或选择性摄取。这 SR-B1:apoA-I 相互作用介导的选择性摄取效率可以是受 HDL 颗粒特性（脂质成分、载脂蛋白内容，或 apoA-I 本身的结构）。这些假设将被检验定义：1) 优选的 HDL 颗粒子群 SR-B1 介导的脂质转移的底物； 2）结构与组成 SR-B1 处理后的 HDL 颗粒（包括 apoA-I 的潜力）蛋白水解）； 3) SR-B1后HDL颗粒的代谢命运加工。了解 SR-B1 在 HDL 代谢中的作用可以定义新的潜在治疗攻击的区域。