Oxysterols, Atherosclerosis and Metabolic Syndrome

动脉粥样硬化是代谢等胰岛素抵抗状态下发病率和死亡率的主要原因 综合症和肥胖症。巨噬细胞脂代谢的调节缺陷在其发病机制中起核心作用。 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酶应答脂质过剩的挑战 激活前馈核受体通路，诱导与脂质有关的转录程序 摄取和外排，并负向调节炎症反应。在最近的研究中，我们已经表明 尼曼-皮克C型(NPC)疾病基因的产物NPC1和NPC2是交付 脂蛋白衍生的胆固醇到细胞内氧甾醇合成的位置。在本提案中，我们将测试 巨噬细胞衍生的氧化甾醇在调节血脂中起关键作用的假说 血管壁的动态平衡。我们认为侧链含氧甾醇合成受阻 会减少胆固醇流出，增加巨噬细胞中的胆固醇积聚，并与 氧化胆固醇水平升高，促进细胞毒性和病变形成。制作特定的产品 巨噬细胞衍生的胆固醇代谢产物可能在调节血浆中起关键作用 通过调节肝脂蛋白合成和/或清除血浆脂蛋白来提高脂蛋白水平。 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NPC1和NPC2功能丧失是否会改变巨噬细胞的氧固醇 合成，从而破坏脂类平衡和促进动脉粥样硬化的小鼠模型， 2)确定巨噬细胞衍生的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NPC1和NPC2功能丧失的嵌合小鼠的水平，以及 3)评估血浆氧固醇水平与冠心病的关系，并确定 患有代谢综合征的人在体重减轻后，氧固醇水平会发生变化。 这些研究将有助于我们理解巨噬细胞衍生的胆固醇的作用。 动脉粥样硬化形成中的代谢物和脂蛋白代谢的调节。这个项目有可能 通过将这些代谢物确定为新的代谢物来改变对代谢综合征患者的护理 检测亚临床动脉粥样硬化性疾病的生物标志物。

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.