Functional Hierarchy of Remnant Lipoprotein Receptors

残余脂蛋白受体的功能层次

• 批准号: 7256767
• 负责人: SERGIO FAZIO
• 金额: $ 2.38万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-01-01 至 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7256767
• 关键词: antiatherogenic agent; apolipoprotein E; atherosclerosis; blood lipoprotein metabolism; bone marrow transplantation; cholesterol; enzyme linked immunosorbent assay; flow cytometry; gene targeting; genetically modified animals; immunocytochemistry; laboratory mouse; low density lipoprotein receptor; macrophage; membrane transport proteins; peroxisome proliferator activated receptor; protein protein interaction; protein structure function; protein transport; receptor binding; receptor expression; scavenger receptor; southern blotting

DESCRIPTION (provided by applicant): During the first cycle of the grant we explored the mechanisms underlying the anti-atherogenic effects of apolipoprotein E (apoE) expressed by macrophages, and delineated a unique hepatic axis between LDL receptor (LDLR) related protein (LRP) and apoE. Because both LRP and apoE are abundantly expressed in the macrophage, we postulate that this axis is operational in the vessel wall as well, where it may direct the uptake of intimal lipoproteins to a specific intracellular routing. Specific aim 1 will address the role of macrophage LRP in atherogenesis. The hypothesis tested is that LRP is the mediator of the anti-atherogenic effects of apoE in the artery wall, and that its deletion will promote lesion growth. Because apoE is a physiologic driver of cholesterol efflux from cells, its anti-atherogenic effects may be mediated by a more complex regulation of cholesterol homeostasis involving both uptake and disposition of macrophage cholesterol. Specific aim 2 will address the effects of apoE receptor binding defective variants expressed by the macrophage on cholesterol efflux and lipoprotein uptake, as well as their interaction with macrophage LRP. The hypothesis tested is that apoE affects cholesterol efflux in vivo not only by acting as an accepter but also by simulating LRP-mediated lipoprotein uptake. Multiple pathways to cholesterol efflux are present in macrophages, and the ATP-binding cassette (ABC) transporters and the scavenger receptor type B1 (SR-B1) can act as channels that deliver cellular cholesterol to extracellular acceptors. ABCA1 transposes phospholipids and cholesterol to apoAI. SR-B1 is normally involved in hepatic HDL cholesterol uptake, but in the macrophage cholesterol can also flow in the opposite direction and result in net efflux. Specific aim 3 will study the mechanism of apoE-mediated cholesterol efflux from macrophages and its relationship, if any, with either ABCA1 or SR-B1. The hypothesis tested is that apoE-mediated cholesterol efflux from macrophages is independent from ABCA1 or SR-B1 mechanisms.

描述（由申请人提供）：在第一轮资助期间，我们探索了巨噬细胞表达的载脂蛋白E（apoE）抗动脉粥样硬化作用的机制，并在LDL受体（LDLR）相关蛋白（LRP）和apoE之间描绘了独特的肝轴。因为LRP和apoE在巨噬细胞中大量表达，我们推测该轴在血管壁中也是可操作的，在那里它可以将内膜脂蛋白的摄取引导到特定的细胞内路线。具体目标1将解决巨噬细胞LRP在动脉粥样硬化形成中的作用。所检验的假设是LRP是动脉壁中apoE的抗动脉粥样硬化作用的介体，并且其缺失将促进病变生长。因为apoE是胆固醇从细胞流出的生理驱动器，所以其抗动脉粥样硬化作用可能通过涉及巨噬细胞胆固醇的摄取和处置的胆固醇稳态的更复杂调节来介导。具体目标2将阐述巨噬细胞表达的apoE受体结合缺陷变体对胆固醇流出和脂蛋白摄取的影响，以及它们与巨噬细胞LRP的相互作用。所检验的假设是apoE不仅通过作为受体而且通过模拟LRP介导的脂蛋白摄取来影响体内胆固醇流出。巨噬细胞中存在多种胆固醇流出途径，ATP结合盒（ABC）转运蛋白和清道夫受体B1型（SR-B1）可作为将细胞胆固醇递送至细胞外受体的通道。ABCA 1将磷脂和胆固醇转座为apoAI。SR-B1通常参与肝脏HDL胆固醇摄取，但在巨噬细胞中，胆固醇也可以沿相反方向流动并导致净流出。具体目标3将研究apoE介导的胆固醇从巨噬细胞流出的机制及其与ABCA 1或SR-B1的关系（如果有的话）。所检验的假设是apoE介导的巨噬细胞胆固醇流出独立于ABCA 1或SR-B1机制。