SR-BI MEDIATED SELECTIVE CHOLESTEROL ESTER UPTAKE

SR-BI 介导的选择性胆固醇酯摄取

• 批准号: 6707547
• 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/6707547
• 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apoA-I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血浆HDL和apoA-I水平相关 与apoA-I的催化速率有关，而不是与apoA-I的产生速率有关。无论是 apoA-I清除位点加速catabolism的机制 已经被清楚地描述了。本建议侧重于以下方面的作用： 高密度脂蛋白受体SR-B1在调节apoA-I分解代谢速率中的作用。SR-B1提供 胆固醇酯通过一个过程，这是根本不同的细胞 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的核心转移到 没有载脂蛋白部分内化的细胞。尽管 无载脂蛋白摄取，肝脏中选择性脂质摄取增加 由SR-B1介导的与apoA-I的催化活性增加有关， 至少有一部分是发生在肾脏。因此，一个中心假设 SR-B1与HDL的相互作用引发了HDL的变化。 一种脂蛋白颗粒，通过一种机制促进随后的catalysis， 独立于SR-B1。SR-B1以高亲和力结合许多不同的 脂蛋白颗粒除了HDL，包括VLDL，LDL，和氧化 低密度脂蛋白SR-B1结合脂蛋白后的重要代谢事件 是CE从颗粒核心到细胞的选择性递送。我们提出 apoA-I是SR-B1介导的选择性摄取的关键配体， 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。的 由SR-B1：apoA-I相互作用介导的选择性摄取的效率可以是 由HDL颗粒（脂质成分、载脂蛋白 内容，或apoA-I本身的结构）。这些假设将由以下人员进行检验： 定义：1）优选的HDL颗粒的亚群 SR-B1介导的脂质转移的底物; 2）结构和组成 经SR-B1处理后的HDL颗粒（包括apoA-I的可能性 蛋白水解）;和3）SR-B1后HDL颗粒的代谢命运 处理.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