Role of Sphingomyelin in Lipoprotein Metabolism

鞘磷脂（SM）是血浆中仅次于磷脂酰胆碱（PC）的最丰富的磷脂， 细胞膜筏的重要组成部分。尽管最近的流行病学研究表明， 血浆中SM水平增加动脉粥样硬化的风险，其潜在机制尚不清楚， SM的正常功能尚未阐明。我们建议，由于其独特的结构， SM定位于细胞的外表面，通过抑制细胞膜的完整性来保护细胞膜。 磷脂酶和脂质过氧化反应。此外，我们建议，由于其亲和力， SM调节细胞胆固醇稳态和逆转胆固醇转运。失调 这些功能可导致炎症并促进动脉粥样硬化。 在目标1中，我们提出了测试SM调节胆固醇逆向转运的假设，重点是 关于其在胆固醇从巨噬细胞中流出以及在LCAT对胆固醇的酯化中的作用。 SM在ABCG 1转运蛋白介导的胆固醇转运过程中充当胆固醇伴侣的新假设 将探索外排。将研究SM在生理系统中调节LCAT的作用。在 目的2，我们将研究SM作为抗炎脂质通过抑制 形成促炎脂质，如溶血PC、花生四烯酸、氧化磷脂和氧化甾醇。 SM竞争性抑制所有利用PC作为底物的酶的假设将用 关于分泌型磷脂酶和内皮脂肪酶。SM在细胞增殖中的抑制作用 将在脂蛋白和细胞膜中测试促炎氧化PC和氧固醇。效果 SM缺乏对巨噬细胞和中性粒细胞功能的影响，包括细胞因子的产生和超氧化物 将在骨髓特异性SM缺陷型小鼠中研究第二代。在目标3中，SM和神经酰胺在 细胞胆固醇稳态将通过确定它们对胆固醇运输的影响来研究 以及细胞与环境之间的联系。这些研究将提供新的 深入了解这种重要磷脂的生理作用，并可能发现新的 针对炎症和动脉粥样硬化的治疗靶点。

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.