Macrophage Cholesterol Efflux During Inflammation

炎症期间巨噬细胞胆固醇流出

• 批准号: 7219728
• 负责人: Nancy R Webb
• 金额: $ 30.27万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-12-01 至 2011-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7219728
• 关键词: ATP-Binding Cassette Transporters; Acute; Acute-Phase Proteins; Acute-Phase Reaction; Affect; Antiatherogenic; Apolipoprotein E; Apolipoproteins; Apolipoproteins A; Arterial Fatty Streak; Atherosclerosis; Binding; Cell membrane; Cells; Charge; Cholesterol; Cholesterol Ester Transfer Proteins; Data; Development; Equilibrium; Excision; Generations; Helix (Snails); High Density Lipoproteins; Human; Immunohistochemistry; In Vitro; Inflammation; Inflammatory; Laboratories; Lead; Lipids; Lipoproteins; Mediating; Mediator of activation protein; Modification; Molecular; Mus; Numbers; Pathogenesis; Phase; Phospholipase A2; Phospholipids; Play; Protein Isoforms; Proteins; Rate; Research Personnel; Role; Serum; Serum amyloid A protein; Structure; System; Testing; atherogenesis; ear helix; extracellular; gain of function; in vivo; loss of function; macrophage; member; particle; prevent; programs; response; reverse cholesterol transport; size; uptake

Macrophages possess a number of mechanisms to regulate the balance between cholesterol uptake/synthesis and export. Of major importance are transport mechanisms that promote the efflux of excess cholesterol to extracellular acceptors. The removal of excess cholesterol is critical in the vessel wall, where macrophage uptake of lipoprotein-derived lipid can lead to a pathological cholesterol load in the absence of sufficient removal systems. Two members of the ATP binding cassette (ABC) superfamily of transmembrane transporters, ABCA1 and ABCG1, play critical roles in preventing cholesterol lipid accumulation in macrophages. Extensive studies have shown that ABCA1 promotes efflux of both cholesterol and phospholipids to lipid-poor apolipoproteins, in particular, apoA-l. In contrast, ABCG1 appears to promote efflux by redistributing intracellular cholesterol to plasma membrane domains accessible for removal by HDL, but not lipid-poor apoA-l. Thus, factors that affect the lipidated state of apoA-l may modulate the activity of these two transporters. During inflammation, HDL undergoes extensive remodeling that leads to the generation of particles that are significantly altered in size, charge, and apolipoprotein and lipid content. These alterations are primarily brought about by the acute phase reactants serum amyloid A (SAA) and Group IIA secretory phospholipase A2. Accumulating evidence from multiple laboratories, including ours, has established that SAA, either delivered as acute phase HDL or in a lipid-free form, can enhance macrophage cholesterol efflux. In Preliminary Data, we provide evidence that in the presence of cholesterol ester transfer protein, phospholipid depletion of HDL particles by Group IIA sPLA2 can lead to the generation of small, lipid-depleted HDL particles. We aim to show that a major consequence of the acute phase response is an increase in the mobilization of cholesterol from the periphery, and an accelerated rate of macrophage reverse cholesterol transport. We hypothesize that SAA and sPLA2 promote macrophage lipid efflux by modifying HDL acceptors and through direct interactions with macrophage cells. To test this hypothesis, we propose the following Specific Aims: 1) To demonstrate that inflammation-induced remodeling of HDL generates substrates that enhance ABCA1 and ABCG1-dependent efflux; 2) To investigate the mechanism(s) by which SAA and sPLA2 promote macrophage cholesterol efflux; and 3) To test the hypothesis that SAA protects against atherosclerotic lipid accumulation through an ABCA1 and/or ABCG1 -dependent mechanism.

巨噬细胞具有许多机制来调节胆固醇之间的平衡， 吸收/综合和输出。其中最重要的是运输机制，促进流出的 过量胆固醇的细胞外受体。去除血管壁中多余的胆固醇是至关重要的， 其中巨噬细胞摄取脂蛋白衍生的脂质可导致 缺乏足够的清除系统。ATP结合盒（ABC）超家族的两个成员是 跨膜转运蛋白ABCA 1和ABCG 1在防止胆固醇脂质过氧化中起关键作用， 在巨噬细胞中积累。广泛的研究表明，ABCA 1促进两种细胞的外排， 胆固醇和磷脂转化为贫脂载脂蛋白，特别是apoA-1。相反，ABCG 1似乎 通过将细胞内胆固醇重新分配到质膜区域， 通过HDL去除，但不通过脂质贫乏的apoA-I去除。因此，影响apoA-1脂化状态的因素可能 调节这两种转运蛋白的活性。在炎症过程中，HDL经历广泛的重塑， 这导致产生在大小、电荷和载脂蛋白方面显著改变的颗粒， 脂质含量这些改变主要是由急性期反应物血清淀粉样蛋白A引起的 (SAA)和IIA族分泌型磷脂酶A2。从多个实验室收集证据， 包括我们的研究，已经确定SAA，无论是作为急性期HDL还是以无脂质形式递送， 增强巨噬细胞胆固醇流出。在初步数据中，我们提供的证据表明，在存在 胆固醇酯转运蛋白，IIA型sPLA 2对HDL颗粒的磷脂消耗可导致 产生小的、脂质耗尽的HDL颗粒。我们的目的是表明，急性的一个主要后果， 时相反应是胆固醇从外周动员的增加， 巨噬细胞胆固醇逆向转运的机制我们推测SAA和sPLA 2促进巨噬细胞 通过修饰HDL受体和通过与巨噬细胞的直接相互作用，脂质流出。为了验证这一 假设，我们提出了以下具体目的：1）为了证明炎症诱导的 HDL的重塑产生增强ABCA 1和ABCG 1依赖性外排的底物; 2） 研究SAA和sPLA 2促进巨噬细胞胆固醇流出的机制;和3） 检验SAA通过ABCA 1和/或 ABCG 1依赖机制。