Role of Sphingomyelin in Lipoprotein Metabolism

鞘磷脂在脂蛋白代谢中的作用

• 批准号: 7893631
• 负责人: PAPASANI V SUBBAIAH
• 金额: $ 39.25万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7893631
• 关键词: Ablation; Acute; Address; Affect; Affinity; Aging; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Ants; Apolipoprotein E; Atherosclerosis; Cardiovascular Diseases; Carrier Proteins; Cell membrane; Cell surface; Cells; Ceramides; Cholesterol; Cholesterol Esters; Cholesterol Homeostasis; Coronary heart disease; Data; Environment; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Enzymes; Epidemiologic Studies; Epidemiology; Esterification; Free Radicals; Funding; Generations; Goals; HDL cholesteryl ester; Hand; Heart Diseases; Human; Hydrolysis; Hyperlipidemia; Inflammation; Inflammatory; Inflammatory Response; Lateral; Lead; Lecithin; Left; Lipase; Lipid Peroxidation; Lipids; Lipoproteins; Low-Density Lipoproteins; Measures; Mediating; Membrane; Metabolism; Methods; Molecular Chaperones; Mus; Myelogenous; Organelles; Pathway interactions; Peripheral; Phase; Phosphatidylcholine-Sterol O-Acyltransferase; Phospholipase; Phospholipids; Physiological; Plasma; Production; Property; Proteins; Publishing; Radio; Reaction; Regulation; Reporting; Resistance; Risk; Risk Factors; Role; Severities; Signal Transduction; Signaling Molecule; Sphingomyelins; Sterol O-Acyltransferase; Sterols; Structure; Superoxides; System; Testing; Therapeutic; Tracer; Unsaturated Fats; Very low density lipoprotein; Work; arachidonate; base; cell growth regulation; cholesterol trafficking; cytokine; fluidity; hepatic lipase; high density lipoprotein sphingomyelin; insight; lipoprotein lipase; macrophage; neutrophil; new therapeutic target; novel; oxidation; oxidized lipid; public health relevance; receptor; reverse cholesterol transport; sterol esterase; trafficking; uptake

DESCRIPTION (provided by applicant): Sphingomyelin (SM) is the most abundant phospholipid in plasma next to phosphatidylcholine (PC), and is an essential component of cell membrane rafts. Although recent epidemiologic studies suggest that high SM levels in plasma increase the risk of atherosclerosis, the underlying mechanisms are unknown, because the normal functions of SM have not been elucidated. We propose that, because of its unique structure, and localization in the outer surface of cells, SM protects the integrity of cell membranes by inhibiting the phospholipase and lipid peroxidation reactions. Furthermore, we propose that because of its affinity to cholesterol, SM regulates cell cholesterol homeostasis and reverse cholesterol transport. Dysregulation of these functions could lead to inflammation and promote atherosclerosis. In Aim 1, we propose to test the hypothesis that SM regulates reverse cholesterol transport, focusing on its role in the efflux of cholesterol from macrophages, and in the esterification of cholesterol by LCAT. The novel hypothesis that SM acts as a chaperone for cholesterol during ABCG1 transporter-mediated efflux will be explored. The role of SM in the regulation of LCAT in physiological systems will be studied. In Aim 2, we will investigate the hypothesis that SM acts as an anti-inflammatory lipid by inhibiting the formation of pro-inflammatory lipids such as lyso PC, arachidonate, oxidized phospholipids and oxysterols. The hypothesis that SM competitively inhibits all enzymes that utilize PC as substrate will be tested with respect to secretory phospholipases and endothelial lipase. The inhibitory role of SM in the generation of pro-inflammatory oxidized PCs and oxysterols will be tested in lipoproteins and cell membranes. The effect of SM deficiency on the macrophage and neutrophil function, including cytokine production and superoxide generation, will be studied in myeloid-specific SM-deficient mice. In Aim 3, the role of SM and ceramide in cellular cholesterol homeostasis will be studied by determining their effects on cholesterol trafficking between cellular compartments and between cells and their environment. These studies will provide novel insights into the physiological role of this important phospholipid, and could possibly identify novel therapeutic targets against inflammation and atherosclerosis. PUBLIC HEALTH RELEVANCE: The studies proposed here will investigate the physiological role of sphingomyelin (SM) a special lipid molecule prevalent in plasma and in outer cell membrane. They will specifically focus on the role of SM as an ant-inflammatory molecule that protects cells against environmental insults. These studies could lead not only to new understanding of mechanisms of inflammation and heart disease, but also to better therapeutic strategies. First, are there any macrophage pathways for cholesterol metabolism that are up- or down regulated by ablation of ABCG1? There could be changes in cellular cholesterol content, cholesterol esterases, ACAT, ABCA1, or possibly SR-B1 that could affect efflux. Second, there are other mechanisms that effect efflux, particularly spontaneous transfer, which Rothblat et al have shown to be important in some contexts (ATVB 2006 26:541-7) and efflux mediated by apo E (ATVB 2006 26:157-62). Lastly, it would be useful to compare efflux with net change in cholesterol by a non radio tracer method that would measure both medium and cellular cholesterol content. Radio tracers reveal how fast FC leaves the cell but not how much unlabeled cholesterol re enters the cell from donors in the medium.

描述（由申请人提供）：鞘磷脂（SM）是磷脂酰胆碱（PC）的血浆中最丰富的磷脂，并且是细胞膜木筏的重要组成部分。尽管最近的流行病学研究表明，血浆中的SM水平较高会增加动脉粥样硬化的风险，但潜在机制尚不清楚，因为SM的正常功能尚未阐明。我们建议，由于其独特的结构以及在细胞外表面的定位，SM通过抑制磷脂酶和脂质过氧化反应来保护细胞膜的完整性。此外，我们建议，由于它与胆固醇的亲和力，SM可以调节细胞胆固醇稳态和反向胆固醇的运输。这些功能的失调可能导致炎症并促进动脉粥样硬化。在AIM 1中，我们建议测试SM调节反向胆固醇转运的假设，重点是其在巨噬细胞中胆固醇外排和在LCAT中胆固醇酯化中的作用。将探讨SM在ABCG1转运蛋白介导的排出过程中充当胆固醇的伴侣的新型假设。将研究SM在LCAT调节生理系统中的作用。在AIM 2中，我们将通过抑制促炎性脂质的形成，例如溶血PC，蛛网膜酸，氧化磷脂和氧甲醇，从而研究SM作为抗炎脂质的假设。 SM竞争性抑制所有利用PC作为底物的酶的假设将在分泌磷脂酶和内皮脂肪酶方面进行测试。 SM在促炎性氧化的PC和氧甲醇的产生中的抑制作用将在脂蛋白和细胞膜中进行测试。 SM缺乏症对巨噬细胞和中性粒细胞功能（包括细胞因子产生和超氧化物产生）的影响将在髓样特异性的SM缺陷型小鼠中进行研究。在AIM 3中，将研究SM和神经酰胺在细胞胆固醇稳态中的作用，通过确定它们对细胞隔室之间以及细胞与其环境之间胆固醇运输的影响来研究。这些研究将提供有关这种重要磷脂的生理作用的新见解，并可能鉴定出针对炎症和动脉粥样硬化的新型治疗靶标。公共卫生相关性：这里提出的研究将研究鞘磷脂（SM）在血浆和外细胞膜中普遍存在的特殊脂质分子的生理作用。他们将特别关注SM作为保护细胞免受环境损伤的蚂蚁炎性分子的作用。这些研究不仅可以引起人们对炎症和心脏病机制的新理解，还可以更好地理解治疗策略。 首先，是否有胆固醇代谢的巨噬细胞途径是由ABCG1消融调节的？细胞胆固醇含量，胆固醇酯酶，ACAT，ABCA1或可能影响SR-B1的细胞胆固醇含量可能会发生变化。其次，还有其他机制影响外排，尤其是自发转移，Rothblat等人在某些情况下已证明这很重要（ATVB 2006 26：541-7），而由APO E介导的外排（ATVB 2006 26：157-62）。最后，通过一种可以测量培养基和细胞胆固醇含量的非无线电示踪剂方法将外排与胆固醇的净变化进行比较将是有用的。无线电示踪剂揭示了FC离开细胞的速度，但没有从培养基中的供体进入细胞的未标记胆固醇。