Functional Hierarchy of Remnant Lipoprotein Receptors

在第一轮资助中，我们探索了抗动脉粥样硬化药物的潜在机制。 巨噬细胞表达的载脂蛋白E（apoE）的影响，并描绘了一个独特的肝细胞凋亡。 低密度脂蛋白受体（LDLR）相关蛋白（LRP）和apoE之间的轴。因为LRP和apoE 在巨噬细胞中大量表达，我们假设该轴在血管中起作用。 也可以通过血管壁，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径。 具体目标1将阐明巨噬细胞LRP在动脉粥样硬化形成中的作用。检验的假设是 LRP是apoE在动脉壁中抗动脉粥样硬化作用的介质， 缺失将促进病变生长。因为apoE是胆固醇流出的生理驱动剂， 细胞，其抗动脉粥样硬化作用可能是通过更复杂的调节胆固醇介导的 涉及巨噬细胞胆固醇摄取和处置的体内平衡。具体目标2将 研究巨噬细胞表达的apoE受体结合缺陷变体对 胆固醇流出和脂蛋白摄取，以及它们与巨噬细胞LRP的相互作用。的 经检验的假设是，apoE在体内不仅作为受体， 也通过模拟LRP介导的脂蛋白摄取。胆固醇流出的多种途径是 存在于巨噬细胞中，ATP结合盒（ABC）转运蛋白和清道夫 受体B1（SR-B1）可以作为通道，将细胞胆固醇传递到细胞外， 接受者ABCA 1将磷脂和胆固醇转座为apoAI。SR-B1通常与 胆固醇在肝脏HDL中摄取，但在巨噬细胞中胆固醇也可流向相反方向 方向和净流出的结果。具体目标3将研究apoE介导的 胆固醇从巨噬细胞流出及其与ABCA 1或SR-B1的关系（如果有的话）。的 假设检验是apoE介导的胆固醇从巨噬细胞流出是独立于 ABCA 1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.