Functional Hierarchy of Remnant Lipoprotein Receptors

残余脂蛋白受体的功能层次

• 批准号: 8875134
• 负责人: SERGIO FAZIO
• 金额: $ 13.73万
• 依托单位: OREGON HEALTH & SCIENCE 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 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8875134
• 关键词: Affect; Antiatherogenic; Apolipoprotein E; Apoptosis; Apoptotic; Arterial Fatty Streak; Automobile Driving; Autophagocytosis; Autophagosome; Back; Binding; Biological; Blood; Blood Vessels; Cell Death; Cell Survival; Cells; Cessation of life; Cholesterol; Cholesterol Esters; Complex; Data; Environment; Excision; Familial Hypercholesterolemia; Foam Cells; Grant; Growth; Health; Hepatic; Homeostasis; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Lead; Lesion; Life; Ligands; Link; Lipid-Laden Macrophage; Lipoprotein (a); Lipoprotein Receptor; Lipoproteins; Liver; Mediating; Membrane; Molecular; Monocytosis; Mus; Myocardial Infarction; NF-kappa B; Necrosis; Pathway interactions; Pattern; Phagocytes; Phagocytosis; Phenotype; Plasma; Prize; Process; Protein Isoforms; Proteins; Regulation; Role; Saposins; Signal Transduction; Sphingolipid Activator Proteins; Sphingolipids; Staging; Stress; Stroke; System; Testing; Tissues; Work; atherogenesis; cholesterol trafficking; in vivo; lipoprotein-remnant receptor; macrophage; monocyte; receptor; receptor internalization; therapeutic development; therapeutic target; trafficking

DESCRIPTION (provided by applicant): The atheroma macrophage lives in a peculiar environment, where cholesterol excesses trigger diverging signals of active phagocytosis and inflammatory bursts. During the previous cycles of this grant, we have focused on two proteins that have both cooperative and independent functions on cellular cholesterol trafficking and regulation of inflammation, apoE and LRP1. ApoE is an LXR-regulated protein, highly expressed in macrophages under conditions of cholesterol loading, with the ability to drive cholesterol efflux from the cell and with direct anti-atherogenic effects. However, apoE can also associate with atherogenic lipoproteins and then bind to internalizing receptors such as LDLR and LRP1, thus driving cholesterol back into the cell. LRP1, a receptor for multiple ligands, acts in the liver as a back-up system for the LDLR to clear remnant lipoproteins. Hepatic LRP1 needs locally produced apoE to clear incoming remnants already enriched in plasma-derived apoE, whereas LDLR clears apoE-containing lipoproteins even in the absence of locally produced apoE. With the working hypothesis that apoE and LRP1 interact more intricately than in a relation between lipoprotein ligand and its internalizing receptor, we moved to an experimental stage where LDLR is not the dominant lipoprotein receptor and where the interaction may have complex biological consequences, the atheroma macrophage. We demonstrated that absence of LRP1 in macrophages increases atherogenesis, a paradoxical effect given that it also reduced internalization of remnant lipoproteins and increased expression of apoE. These data suggest both that the effect of LRP1 is not linked to bulk cholesterol transport and that the vascular effect of apoE is mediated by an interaction with LRP1. We were surprised to determine that the latter is not true, as the deletion of apoE aggravated the atherogenic phenotype of LRP1-/- macrophages, thus suggesting that these proteins have independent and additive effects that regulate vascular homeostasis. The plaques of apoE-/-/LRP1-/- mice showed a uniquely severe pattern of macrophage apoptosis with a deficit in the internalization of apoptotic bodies by viable phagocytes. An effect unique to LRP1 was noted on the induction of inflammatory responses, as mice carrying LRP1-/- macrophages showed significantly higher numbers of circulating and splenic pro-inflammatory Ly6chi monocytes and arterial wall Ly6chi and CCR2 positive macrophages. Another effect unique to LRP1 was noted on the regulation of prosaposin trafficking. Prosaposin leads to the formation of the saposins (sphingolipid activator proteins), critical for processing and clearance of lysosomal and membrane sphingolipids. This pathway is intertwined with the autophagic machinery, recently shown to regulate cholesterol efflux from foam cells, and with the inflammatory response. The proposed studies aim at characterizing the molecular pathways responsible for the exaggerated cell death, inflammation, and dysfunctional clearance of cell debris caused by the absence of LRP1. We strive to understand the factors that regulate bulk plaque regression.

描述(申请人提供)：动脉粥样硬化巨噬细胞生活在一个特殊的环境中，胆固醇过量会触发活跃的吞噬和炎症爆发的不同信号。在这笔赠款的前几个周期中，我们重点研究了两种在细胞胆固醇运输和炎症调节方面既具有合作功能又具有独立功能的蛋白质，即apoE和LRP1。载脂蛋白E是一种受LXR调节的蛋白，在胆固醇负荷的条件下在巨噬细胞中高表达，具有推动胆固醇流出细胞的能力，并具有直接抗动脉粥样硬化的作用。然而，apoE也可以与致动脉粥样硬化的脂蛋白结合，然后与内化受体如LDLR和LRP1结合，从而将胆固醇驱回细胞内。LRP1是一种多配体受体，在肝脏中作为LDLR清除残余脂蛋白的备份系统。肝脏LRP1需要局部产生的载脂蛋白E来清除已经富含血浆来源的载脂蛋白E的残留物，而LDLR即使在没有局部产生的载脂蛋白E的情况下也会清除含有载脂蛋白E的脂蛋白。在假设载脂蛋白E和LRP1之间的相互作用比脂蛋白配体和其内化受体之间的关系更复杂的情况下，我们进入了一个实验阶段，在这个阶段，LDLR不是主要的脂蛋白受体，并且这种相互作用可能具有复杂的生物学后果，即动脉粥样硬化巨噬细胞。我们证明，巨噬细胞中缺乏LRP1会增加动脉粥样硬化的形成，这是一种矛盾的效应，因为它还减少了残余脂蛋白的内化，增加了apoE的表达。这些数据表明，LRP1的作用与大量胆固醇的转运无关，而apoE的血管作用是通过与LRP1的相互作用来介导的。我们惊讶地发现后者不是真的，因为apoE的缺失加剧了LRP1-/-巨噬细胞的动脉粥样硬化表型，从而表明这些蛋白具有调节血管内稳态的独立和相加的作用。ApoE-/-/LRP1-/-小鼠的斑块表现出一种独特的严重的巨噬细胞凋亡模式，并缺乏活性吞噬细胞对凋亡小体的内化。LRP1在诱导炎症反应方面有一种独特的作用，因为携带LRP1-/-巨噬细胞的小鼠显示出循环和脾内促炎症的Ly6chi单核细胞以及动脉壁Ly6chi和CCR2阳性巨噬细胞的数量显著增加。LRP1所特有的另一个影响是管制异丙皂苷贩运。异丙皂苷导致皂苷(鞘脂激活蛋白)的形成，对溶酶体和膜鞘脂的加工和清除至关重要。这一途径与自噬机制交织在一起，最近发现自噬机制调节泡沫细胞的胆固醇外流，并与炎症反应交织在一起。拟议的研究旨在描述由于缺乏LRP1而导致细胞过度死亡、炎症和细胞碎片清除功能障碍的分子途径。我们努力了解调节大块斑块消退的因素。