Oxysterols, Atherosclerosis and Metabolic Syndrome

动脉粥样硬化是胰岛素抵抗状态，如代谢紊乱， 综合征和肥胖症。巨噬细胞脂质代谢的调节缺陷在巨噬细胞凋亡中起核心作用。 与这些血脂异常状态相关的血管病变的发展。在动脉粥样硬化形成过程中， 巨噬细胞通过酶促产生氧固醇来响应脂质过量的挑战， 激活前馈核受体途径，其诱导参与脂质的转录程序 摄取和流出，并负调节炎症反应。在最近的研究中，我们已经表明， 尼曼-匹克C型（NPC）疾病基因的产物NPC 1和NPC 2是递送 脂蛋白衍生的胆固醇到细胞内氧固醇合成的位点。在本提案中，我们将测试 巨噬细胞源性氧化固醇在脂质调节中起关键作用的假说 维持血管壁的内稳态我们认为侧链含氧甾醇的合成受损 将减少胆固醇流出并增加巨噬细胞中的胆固醇积累， 氧化胆固醇水平增加，促进细胞毒性和损伤形成。产生特异性 巨噬细胞衍生的胆固醇代谢物还可能在控制血浆中起关键作用， 通过调节肝脂蛋白合成和/或血浆脂蛋白的清除来调节脂蛋白水平。 这一假设将通过以下具体目标进行检验： 1)确定巨噬细胞特异性NPC 1和NPC 2功能丧失是否改变巨噬细胞氧化固醇 合成，从而在鼠模型中破坏脂质稳态并促进动脉粥样硬化， 2)确定巨噬细胞源性胆固醇代谢产物是否影响血浆脂蛋白的调节 巨噬细胞特异性NPC 1和NPC 2功能丧失的嵌合小鼠中的水平，以及 3)评价血浆氧固醇水平与冠心病的关系， 代谢综合征患者体重减轻后氧固醇水平发生变化。 这些研究将有助于我们理解巨噬细胞源性胆固醇的作用 代谢产物在动脉粥样硬化形成和调节脂蛋白代谢中的作用。该项目有可能 通过将这些代谢物确定为新的代谢物， 用于检测亚临床动脉粥样硬化疾病的生物标志物。

Atheroclerosis is a major cause of morbidity and mortality in insulin-resistant states such as metabolic syndrome and obesity. Defective regulation of macrophage lipid metabolism plays a central role in the development of vascular lesions associated with these dyslipidemic states. During atherogenesis, macrophages respond to the challenge of lipid excess through enzymatic production of oxysterols and activation of feed-forward nuclear receptor pathways that induce transcriptional programs involved in lipid uptake and efflux, and negatively regulate inflammatory responses. In recent studies, we have shown that the products of the Niemann-Pick type C (NPC) disease genes, NPC1 and NPC2, are required for delivery of lipoprotein-derived cholesterol to sites of intracellular oxysterol synthesis. In this proposal, we will test the hypothesis that macrophage-derived oxysterols play a critical role in the regulation of lipid homeostasis in the vascular wall. We propose that impaired synthesis of side-chain oxygenated sterols will reduce cholesterol efflux and increase cholesterol accumulation in macrophages, and, in concert with increased levels of oxidized cholesterol, promote cytotoxicity and lesion formation. Production of specific macrophage-derived cholesterol metabolites additionally may play a critical role in governing plasma lipoprotein levels through regulation of hepatic lipoprotein synthesis and/or clearance of plasma lipoproteins. This hypothesis will be tested by the following specific aims: 1) To determine whether macrophage-specific NPC1 and NPC2 loss of function alters macrophage oxysterol synthesis, thereby disrupting lipid homeostasis and promoting atherosclerosis in a murine model, 2) To determine whether macrophage-derived cholesterol metabolites affect regulation of plasma lipoprotein levels in chimeric mice with macrophage-specific NPC1 and NPC2 loss of function, and 3) To assess the relationship between plasma oxysterol levels and coronary heart disease and determine if oxysterol levels change following weight loss in humans with the metabolic syndrome. These studies will contribute to our understanding of the role of macrophage-derived cholesterol metabolites in atherogenesis and regulation of lipoprotein metabolism. This project has the potential to transform the care of people with the metabolic syndrome by establishing these metabolites as novel biomarkers for detection of subclinical atherosclerotic disease.