SR-BI MEDIATED SELECTIVE CHOLESTEROL ESTER UPTAKE

SR-BI 介导的选择性胆固醇酯摄取

• 批准号: 6866412
• 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/6866412
• 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：有兴趣了解调节高密度脂蛋白的因素 和载脂蛋白A-I水平，因为这些水平与患糖尿病的风险呈负相关 动脉粥样硬化性血管疾病。血浆高密度脂蛋白和载脂蛋白A-I水平相关 与apoA-I分解代谢的速率有关，而不是apoA-I的生成。既不是 加速分解代谢的机制和载脂蛋白A-I的清除部位(S) 已经清楚地描绘了来自等离子体的物质。这项建议侧重于 高密度脂蛋白受体SR-B1在调节载脂蛋白A-I分解代谢率中的作用。SR-B1提供 通过一种从根本上不同于 受体介导的内吞作用。在这个过程中，高密度脂蛋白与SR-B1在 并将胆固醇酯从颗粒的核心转移到细胞表面 未内化载脂蛋白部分的细胞。尽管 肝脏缺乏载脂蛋白摄取，选择性脂质摄取增加 由SR-B1介导的与apoA-I分解代谢增加相关，并且在 这种分解代谢中至少有一部分发生在肾脏。因此，一个中心假设 这一建议的主要内容是，SR-B1与高密度脂蛋白的相互作用引发了 促进后续分解代谢的脂蛋白颗粒，其机制是 独立于SR-B1。SR-B1以高亲和力结合许多不同的 除高密度脂蛋白外的脂蛋白颗粒，包括极低密度脂蛋白、低密度脂蛋白和氧化 低密度脂蛋白。SR-B1与脂蛋白结合后的重要代谢事件 是将CE从颗粒的核心选择性地输送到细胞。我们建议 ApoA-I是SR-B1介导的选择性摄取的关键配体，并且 高密度脂蛋白颗粒上的apoA-I构象可影响其与 SR-B1阻碍或促进受体结合和/或选择性摄取。这个 SR-B1介导的选择性摄取效率：apoA-I相互作用可以是 受高密度脂蛋白颗粒(脂成分、载脂蛋白)特性的调节 内容，或载脂蛋白A-I本身的结构)。这些假设将通过以下方式进行验证 定义：1)首选的高密度脂蛋白颗粒的亚群 SR-B1介导的脂质转移的底物；2)结构和成分 经SR-B1处理后的高密度脂蛋白颗粒(包括apoA-I的可能性 蛋白质分解)；以及3)SR-B1后高密度脂蛋白颗粒的代谢去向 正在处理。了解SR-B1在高密度脂蛋白代谢中的作用可以定义新的 潜在的治疗性攻击的区域。

项目成果

ApoB-containing lipoproteins in apoE-deficient mice are not metabolized by the class B scavenger receptor BI.

apoE 缺陷小鼠中含有 ApoB 的脂蛋白不被 B 类清道夫受体 BI 代谢。

• DOI: 10.1194/jlr.m300319-jlr200
• 发表时间: 2004
• 期刊: Journal of lipid research
• 影响因子: 6.5
• 作者: Webb,NancyR;deBeer,MariaC;deBeer,FrederickC;vanderWesthuyzen,DeneysR
• 通讯作者: vanderWesthuyzen,DeneysR

SR-BI-mediated selective lipid uptake segregates apoA-I and apoA-II catabolism.

SR-BI 介导的选择性脂质摄取分离 apoA-I 和 apoA-II 分解代谢。

• DOI: 10.1194/jlr.m500068-jlr200
• 发表时间: 2005
• 期刊: Journal of lipid research
• 影响因子: 6.5
• 作者: deBeer,MariaC;vanderWesthuyzen,DeneysR;Whitaker,NathanL;Webb,NancyR;deBeer,FrederickC
• 通讯作者: deBeer,FrederickC