Functional Hierarchy of Remnant Lipoprotein Receptors

描述（由申请人提供）：在资助的第一个周期中，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）和载脂蛋白E之间描绘了一条独特的肝轴。由于LRP和apoE都在巨噬细胞中大量表达，我们假设这条轴在血管壁中也有作用，它可能指导内膜脂蛋白的摄取到特定的细胞内路径。具体目的1将探讨巨噬细胞LRP在动脉粥样硬化中的作用。经检验的假设是，LRP是动脉壁apoE抗动脉粥样硬化作用的中介，其缺失会促进病变的生长。由于apoE是细胞中胆固醇外排的生理驱动因素，其抗动脉粥样硬化作用可能是由一种更复杂的胆固醇稳态调节介导的，包括巨噬细胞胆固醇的摄取和处置。特异性目标2将探讨巨噬细胞表达的apoE受体结合缺陷变异对胆固醇外溢和脂蛋白摄取的影响，以及它们与巨噬细胞LRP的相互作用。经检验的假设是，apoE影响体内胆固醇外排，不仅作为受体，而且通过模拟lrp介导的脂蛋白摄取。巨噬细胞中存在多种胆固醇外排途径，atp结合盒（ABC）转运体和清道夫受体类型B1 （SR-B1）可以作为将细胞胆固醇传递到细胞外受体的通道。ABCA1将磷脂和胆固醇转位为载脂蛋白ai。SR-B1通常参与肝脏HDL胆固醇摄取，但在巨噬细胞中，胆固醇也可向相反方向流动，导致净外排。特异性目的3将研究apoe介导的巨噬细胞胆固醇外排的机制及其与ABCA1或SR-B1的关系（如果有的话）。经检验的假设是，apoe介导的巨噬细胞胆固醇外排不依赖于ABCA1或SR-B1机制。

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.