SR-BI MEDIATED SELECTIVE CHOLESTEROL ESTER UPTAKE

SR-BI 介导的选择性胆固醇酯摄取

• 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
• 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

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 和人类中的apoa-i级别，因为这些水平与 动脉粥样硬化血管疾病。 HDL和APOA-I的血浆水平相关 达到ApoA-I分解代谢的速率，而不是ApoA-I产生。也不是 加速分解代谢的基础机制或apoA-i删除的位点 从血浆中清楚地描述了。该提议着重于 HDL受体SR-B1在调节ApoA-I分解代谢率方面。 SR-B1提供 通过从根本上与众不同的过程 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粒子的核心转移到 无载脂蛋白部分内在化的细胞。尽管有 缺乏载脂蛋白吸收，肝脏中选择性脂质摄取增加 由SR-B1介导的APOA-I分解代谢增加，并且在 这种分解代谢至少发生在肾脏中。因此，中心假设 该提案是SR-B1与HDL的相互作用启动了 脂蛋白颗粒通过一种机制促进随后的分解代谢 独立于SR-B1。 SR-B1与高亲和力结合了许多不同的 除HDL以外，脂蛋白颗粒（包括VLDL，LDL）和氧化 LDL。 SR-B1结合脂蛋白结合后的重要代谢事件 是从颗粒的核心到细胞的选择性递送。我们建议 ApoA-I是SR-B1介导的选择性吸收的关键配体，并且 HDL粒子上的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介导的选择性吸收的效率：ApoA-I相互作用可以是 由HDL颗粒的性质调节（脂质组成，载脂蛋白 内容，或apoa-i本身的结构）。这些假设将通过 定义：1）首选的HDL颗粒的子群 SR-B1介导的脂质转移的底物； 2）结构和组成 通过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 潜在的治疗攻击区域。