Functional Hierarchy of Remnant Lipoprotein Receptors

在赠款的第一个周期中，我们探索了抗动脉粥样硬化的潜在机制 载脂蛋白E(ApoE)在巨噬细胞表达的作用，并描绘出一个独特的肝脏 低密度脂蛋白受体(LDLR)相关蛋白(LRP)和载脂蛋白E之间的轴。因为LRP和apoE 在巨噬细胞中大量表达，我们推测这个轴在血管中是可操作的 WALL也是如此，在那里它可能引导内膜脂蛋白的摄取到特定的细胞内路线。 具体目标1将阐述巨噬细胞LRP在动脉粥样硬化形成中的作用。经过检验的假设是 LRP是载脂蛋白E在动脉壁抗动脉粥样硬化作用的介体，其 缺失会促进病变的生长。因为apoE是胆固醇外流的生理驱动因素 细胞，其抗动脉粥样硬化的作用可能是通过更复杂的胆固醇调节来实现的。 包括巨噬细胞胆固醇摄取和处置的动态平衡。特定目标2将 探讨巨噬细胞表达的载脂蛋白E受体结合缺陷变异体对血管内皮生长因子的影响 胆固醇外流和脂蛋白摄取，以及它们与巨噬细胞LRP的相互作用。这个 经检验的假设是，载脂蛋白E不仅通过作为受体影响体内的胆固醇外流，而且 也是通过模拟LRP介导的脂蛋白摄取。胆固醇外流的多种途径有 存在于巨噬细胞、三磷酸腺苷结合盒(ABC)转运体和清道夫 受体B1(SR-B1)可以作为将细胞内胆固醇输送到细胞外的通道 接受者。ABCA1将磷脂和胆固醇转位为载脂蛋白AI。通常涉及SR-B1 在肝脏中摄取高密度脂蛋白，但在巨噬细胞中胆固醇也可以相反地流动 方向和结果为净流出。特殊目标3将研究载脂蛋白E介导的机制 巨噬细胞的胆固醇外流及其与ABCA1或SR-B1的关系。这个 经检验的假设是，载脂蛋白E介导的胆固醇从巨噬细胞流出不依赖于 ABCA1或SR-B1机制。

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 accepters. 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.