Macrophage, ABCA1, Inflammation, and Atherosclerosis

巨噬细胞、ABCA1、炎症和动脉粥样硬化

• 批准号: 8277087
• 负责人: JOHN S PARKS
• 金额: $ 36.63万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8277087
• 关键词: ATP-Binding Cassette Transporters; Address; Affect; Agonist; Anti-Inflammatory Agents; Anti-inflammatory; Apolipoprotein A-I; Apoptosis; Apoptotic; Arterial Fatty Streak; Arteries; Atherogenic Diet; Atherosclerosis; Back; Body Composition; Cell membrane; Cells; Cholesterol; Cholesterol Esters; Chronic; Data; Development; Diet; Disease; Eating; Energy Metabolism; Excretory function; Fatty Liver; Fatty acid glycerol esters; Gene Expression; Genetic; Goals; Hepatic; High Density Lipoproteins; Hypersensitivity; Infiltration; Inflammation; Inflammatory; Insulin Resistance; Knock-out; Knockout Mice; Knowledge; Lesion; Lipids; Lipoproteins; Liver; Low Density Lipoprotein Receptor; Membrane; Membrane Microdomains; Membrane Proteins; Metabolic; Mus; Natural Immunity; Necrosis; Obesity; Pathogenesis; Peripheral; Phenotype; Phospholipids; Plasma; Process; Publishing; Relative (related person); Research; Role; Signal Transduction; Site; Sucrose; TLR4 gene; Tangier Disease; Tissues; Toll-like receptors; Weight Gain; Wild Type Mouse; adapter protein; base; cell type; cholesterol transporters; feeding; glucose metabolism; in vivo; insulin signaling; lipid metabolism; macrophage; novel; premature atherosclerosis; public health relevance; reverse cholesterol transport

DESCRIPTION (provided by applicant): ATP binding cassette transporter A1 (ABCA1) is a membrane protein that is required to remove excess lipid from macrophages. Recent data have suggested that macrophage ABCA1 expression is anti-inflammatory and protects against development of insulin resistance. However, since Abca1 is expressed in nearly all tissues in the body, it is difficult to determine the specific role of macrophage Abca1 with regard to inflammation, atherosclerosis development, and insulin resistance. To address these gaps in knowledge, we have developed a macrophage-specific Abca1 knockout (MSKO) mouse. Our goal is to use these mice to determine the mechanisms by which macrophage-specific deletion of Abca1 expression: 1) increases macrophage inflammation, 2) affects atherosclerosis development, and 3) increases development of obesity and insulin resistance. We have found that macrophages from MSKO mice are hypersensitive to Toll-like receptor (TLR) agonists, which appears related to an increase in membrane free cholesterol and lipid rafts. In Specific aim 1, we hypothesize that macrophages from MSKO mice have an i , resulting in increased TLR and adapter protein recruitment into lipid rafts, increased signaling efficiency, , and a pro-inflammatory state. 2) the distribution of TLR4 and adapter proteins in lipid raft vs. non-raft membrane regions 1 TLR4 stimulation. Based on preliminary studies, we hypothesize in Specific aim 2 that atherosclerotic lesions in MSKO mice in the low density lipoprotein receptor (LDLr) KO background have fewer macrophages that are CE-enriched relative to LDLrKO mice, resulting in a similar degree of atherosclerosis. We will determine: 1) plasma lipoprotein phenotype, 2) in vivo reverse cholesterol transport from macrophages, 3) atherosclerosis extent, 4) aortic lesion macrophage number, lipid content, and gene expression, and 5) effect on MSKO-LDLrKO and LDLrKO mice fed an atherogenic diet. In Specific aim 3, our preliminary data demonstrated that MSKO mice fed a high fat/high sucrose (HF/HS) diet have increased body weight, increased hepatic lipid content, and systemic insulin resistance compared to WT mice. We hypothesize that the HF/HS diet results in pro-inflammatory macrophages that reduce insulin signaling and increase fat storage in peripheral tissues and liver. Using HF/HS diet-fed WT and MSKO mice ' , we will determine plasma lipid/lipoprotein phenotype, macrophage inflammatory state and infiltration into tissues, whole body metabolic phenotype, and insulin signaling in liver and peripheral tissues. Results from these studies will fill gaps in knowledge on the specific role of macrophage-specific Abca1 expression in vivo in the pathogenesis of chronic inflammatory diseases such as atherosclerosis, insulin resistance and obesity. PUBLIC HEALTH RELEVANCE: Chronic inflammation results in obesity and insulin resistance. In this proposal, we seek to understand the relationship between macrophage inflammation that results from the specific deletion of a membrane cholesterol transporter on development of atherosclerosis, obesity and insulin resistance.

描述（由申请人提供）：ATP 结合盒转运蛋白 A1 (ABCA1) 是一种膜蛋白，需要从巨噬细胞中去除多余的脂质。最近的数据表明，巨噬细胞 ABCA1 的表达具有抗炎作用，可以防止胰岛素抵抗的发生。然而，由于 Abca1 几乎在体内所有组织中表达，因此很难确定巨噬细胞 Abca1 在炎症、动脉粥样硬化发展和胰岛素抵抗方面的具体作用。为了解决这些知识空白，我们开发了巨噬细胞特异性 Abca1 敲除 (MSKO) 小鼠。我们的目标是利用这些小鼠来确定巨噬细胞特异性删除 Abca1 表达的机制：1) 增加巨噬细胞炎症，2) 影响动脉粥样硬化的发展，3) 增加肥胖和胰岛素抵抗的发展。我们发现 MSKO 小鼠的巨噬细胞对 Toll 样受体 (TLR) 激动剂高度敏感，这似乎与无膜胆固醇和脂筏的增加有关。在具体目标 1 中，我们假设 MSKO 小鼠的巨噬细胞具有 i ，从而导致 TLR 和接头蛋白招募到脂筏中增加，信号传导效率提高，以及促炎状态。 2) TLR4 和接头蛋白在脂筏与非筏膜区域中的分布 1 TLR4 刺激。基于初步研究，我们在具体目标 2 中假设，低密度脂蛋白受体 (LDLr) KO 背景下的 MSKO 小鼠的动脉粥样硬化病变相对于 LDLrKO 小鼠，富含 CE 的巨噬细胞较少，从而导致相似程度的动脉粥样硬化。我们将确定：1) 血浆脂蛋白表型，2) 体内逆转巨噬细胞胆固醇转运，3) 动脉粥样硬化程度，4) 主动脉病变巨噬细胞数量、脂质含量和基因表达，以及 5) 对饲喂致动脉粥样硬化饮食的 MSKO-LDLrKO 和 LDLrKO 小鼠的影响。在具体目标 3 中，我们的初步数据表明，与 WT 小鼠相比，饲喂高脂肪/高蔗糖 (HF/HS) 饮食的 MSKO 小鼠体重增加、肝脂质含量增加和全身胰岛素抵抗。我们假设 HF/HS 饮食会产生促炎巨噬细胞，从而减少胰岛素信号传导并增加周围组织和肝脏的脂肪储存。使用 HF/HS 饮食喂养的 WT 和 MSKO 小鼠，我们将确定血浆脂质/脂蛋白表型、巨噬细胞炎症状态和组织浸润、全身代谢表型以及肝脏和外周组织中的胰岛素信号传导。这些研究的结果将填补关于体内巨噬细胞特异性 Abca1 表达在动脉粥样硬化、胰岛素抵抗和肥胖等慢性炎症性疾病发病机制中的具体作用的知识空白。 公共卫生相关性：慢性炎症会导致肥胖和胰岛素抵抗。在本提案中，我们试图了解膜胆固醇转运蛋白的特异性缺失导致的巨噬细胞炎症与动脉粥样硬化、肥胖和胰岛素抵抗的发展之间的关系。