Functional Hierarchy of Remnant Lipoprotein Receptors

残余脂蛋白受体的功能层次

• 批准号: 7888324
• 负责人: SERGIO FAZIO
• 金额: $ 38.38万
• 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 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7888324
• 关键词: Affinity; Anti-Inflammatory Agents; Anti-inflammatory; Antiatherogenic; Apolipoprotein E; Apoptosis; Apoptotic; Area; Arterial Fatty Streak; Arterial Intimas; Atherosclerosis; Attenuated; Cells; Cholesterol; Cholesterol Homeostasis; Complex; Coronary; Development; Evolution; Excision; Fatty acid glycerol esters; Foam Cells; Grant; High Density Lipoproteins; Homeostasis; Human; Inflammation; Knowledge; LDL-Receptor Related Protein 1; Lead; Lesion; Lipids; Lipoprotein Receptor; Lipoproteins; Low-Density Lipoproteins; Mediating; Mus; Myocardial Infarction; Myocardial Ischemia; Pathway interactions; Phagocytes; Pharmaceutical Preparations; Phenotype; Plasma; Proteins; Regulation; Role; Route; Signal Transduction; Sphingolipids; Stroke; System; Testing; Variant; Very low density lipoprotein; Work; apolipoprotein E-3; apolipoprotein E-4; atherogenesis; base; cell type; cholesterol trafficking; feeding; human disease; improved; in vivo; lipoprotein-remnant receptor; macrophage; mouse model; new therapeutic target; oxidation; receptor; receptor binding; response; reverse cholesterol transport; therapeutic development; trafficking; uptake; vascular inflammation

DESCRIPTION (provided by applicant): The evolution of the atherosclerotic plaque is regulated by the ability of its cells to dispose of excess cholesterol before apoptosis ensues. Macrophages are the dominant cell type of early plaques in humans and mice, and can utilize several pathways for lipoprotein internalization and for cholesterol efflux. Because cholesterol efflux is activated by delivery of lipoprotein-derived oxysterols to LXR, it is possible that different internalizing receptors may induce different macrophage responses to the same cholesterol load. Apolipoprotein (apo)E, a multifunctional protein highly expressed by macrophages and under LXR control, has strong anti-atherogenic effects that can be mediated by its interactions with internalizing receptors, such LDLR and LRP1, or with agents of cholesterol efflux, such as ABCA1 and PLTP. In the previous cycle of this grant, we discovered that LRP1 deletion from macrophages leads to increased apoE synthesis and, surprisingly, increased lesion formation. This suggests that apoE cannot exert its beneficial effects without LRP1. We also identified a functional interaction between apoE and LRP1 controlling the secretory efficiency of macrophage apoE, and determined that human apoE variants expressed by macrophages associate differently with LRP1 and have profoundly different effects on atherogenesis. Finally, we provided evidence for a role of apoE in macrophage cholesterol efflux even in the presence of excess amounts of apoAI, the canonical activator of the HDL pathway. Our results are compatible with a scenario where apoE and LRP1 work in a functional axis to maximize the adaptive responses of atheroma foam cells to the tremendous cholesterol burden in the arterial intima. In this new proposal, we plan to: 1) Demonstrate that the interaction between apoE and LRP1 in macrophages influences lesion formation in mouse models of atherosclerosis; 2) Test the hypothesis that LRP1-mediated internalization of apoE-enriched lipoproteins improves trafficking of cholesterol to efflux- accessible compartments and enhances LXR response; 3) Determine whether LRP1 signaling is responsible for anti-inflammatory and pro-survival counter-regulation in macrophages through cholesterol-dependent and independent mechanisms. Our studies aim at unlocking the fundamental regulation of cholesterol release from lesion macrophages into the HDL pathway as a platform for the development of therapeutics for plaque regression and control of ischemic heart disease. Our studies focus on the mechanisms leading to the accumulation and removal of cholesterol from the atherosclerotic plaque, which is the common cause of heart attacks and strokes. Whereas current medications can reduce the accumulation of cholesterol in the plaque by reducing plasma LDL levels, no therapies are available to induce exit of cholesterol from the plaque. We have discovered a functional connection between two proteins (apoE and LRP1) that improves cholesterol disposal in plaque macrophages, and may lead to development of new drugs for regression of coronary plaques.

描述（由申请人提供）：动脉粥样硬化斑块的演变受其细胞在凋亡启动前处理过量胆固醇的能力调节。巨噬细胞是人类和小鼠早期斑块的主要细胞类型，可以利用几种途径进行脂蛋白内化和胆固醇流出。由于胆固醇流出是通过将脂蛋白衍生的氧固醇递送至LXR来激活的，因此不同的内化受体可能会诱导对相同胆固醇负荷的不同巨噬细胞应答。载脂蛋白（apo）E是一种由巨噬细胞高度表达并受LXR控制的多功能蛋白质，具有很强的抗动脉粥样硬化作用，可通过其与内化受体（如LDLR和LRP 1）或胆固醇外排剂（如ABCA 1和PLTP）的相互作用介导。在该资助的前一个周期中，我们发现巨噬细胞中的LRP 1缺失导致apoE合成增加，令人惊讶的是，增加了病变的形成。这表明apoE在没有LRP 1的情况下不能发挥其有益作用。我们还确定了apoE和LRP 1之间的功能相互作用，控制巨噬细胞apoE的分泌效率，并确定巨噬细胞表达的人类apoE变体与LRP 1的关联不同，对动脉粥样硬化形成有着截然不同的影响。最后，我们提供了证据，即使在存在过量的apoAI，HDL途径的典型激活剂的情况下，apoE在巨噬细胞胆固醇流出中的作用。我们的研究结果与apoE和LRP 1在功能轴中工作以最大化动脉粥样硬化泡沫细胞对动脉内膜中巨大胆固醇负荷的适应性反应的情况是相容的。在这个新的提议中，我们计划：1）证明巨噬细胞中apoE和LRP 1之间的相互作用影响动脉粥样硬化小鼠模型中的病变形成; 2）测试LRP 1介导的富含apoE的脂蛋白的内化改善胆固醇向流出可及区室的运输并增强LXR反应的假设; 3）确定LRP 1信号传导是否通过胆固醇依赖性和非依赖性机制负责巨噬细胞中的抗炎和促存活反调节。我们的研究旨在解锁从病变巨噬细胞到HDL途径的胆固醇释放的基本调节，作为开发斑块消退和缺血性心脏病控制疗法的平台。我们的研究集中在导致胆固醇从动脉粥样硬化斑块中积累和清除的机制上，这是心脏病发作和中风的常见原因。尽管目前的药物可以通过降低血浆LDL水平来减少胆固醇在斑块中的积累，但没有可用于诱导胆固醇从斑块中排出的疗法。我们发现了两种蛋白质（apoE和LRP 1）之间的功能联系，可以改善斑块巨噬细胞中的胆固醇处理，并可能导致开发用于消退冠状动脉斑块的新药。