PGC-1beta in the Regulation of Hepatic Lipid Metabolism

描述（由申请人提供）：代谢综合征正在成为一种全球流行病。这种综合征中的严重代谢失调通常表现为几种疾病的聚集，包括肥胖症、2型糖尿病和血脂异常，并且与心血管疾病风险增加相关。肝脏脂肪生成和脂蛋白代谢在维持脂质稳态中起重要作用。越来越多的证据表明，肝脏脂质代谢在代谢综合征（包括高脂血症、高血糖症和胰岛素抵抗）的关键方面的发病机制中起重要作用。我们最近证明，转录辅激活因子PGC-1？协调调节肝脏中的脂肪生成、脂质运输和脂蛋白代谢。这些数据表明，PGC-1？是维持脂质体内平衡的调节网络的核心组成部分。这项建议的主要目标是测试的假设，PGC-1？参与代谢综合征的发病机制，并作为脂质代谢和胰岛素抵抗之间的分子联系。此外，分子组成的PGC-1？路径将被解剖和分析。目的一是确定和评价PGC-1的作用。在代谢失调的发病机制中以及在将脂质代谢与胰岛素抵抗联系起来方面。目的2是确定转录组件PGC-1？调节甘油三酯和脂蛋白代谢。目的3探讨染色质重构在脂质代谢中的作用。完成这一建议将定义一个主要的调节网络在维持脂质稳态的分子细节。

DESCRIPTION (provided by applicant): Metabolic syndrome is emerging as a global epidemic. The profound metabolic dysregulation in this syndrome is typically manifested by clustering of several disorders, including obesity, type 2 diabetes, and dyslipidemia, and is associated with an increased risk for cardiovascular disease. Hepatic lipogenesis and lipoprotein metabolism are important in maintaining lipid homeostasis. There is increasing evidence that hepatic lipid metabolism plays an important role in the pathogenesis of key aspects of metabolic syndrome, including hyperlipidemia, hyperglycemia, and insulin resistance. We have recently demonstrated that transcriptional coactivator PGC-1? coordinately regulates lipogenesis, lipid trafficking, and lipoprotein metabolism in the liver. These data suggest that PGC-1? is a central component of the regulatory network in maintaining lipid homeostasis. The major goals of this proposal are to test the hypothesis that PGC-1? is involved in the pathogenesis of metabolic syndrome and serves as a molecular link between lipid metabolism and insulin resistance. In addition, molecular components of the PGC-1? pathway will be dissected and analyzed. Aim 1 is to determine evaluate the role of PGC-1? in the pathogenesis of metabolic dysregulation and in linking lipid metabolism to insulin resistance. Aim 2 is to define transcriptional components underlying PGC-1? regulation of triglyceride and lipoprotein metabolism. Aim 3 is to investigate the role of chromatin remodeling in lipid metabolism. Completion of this proposal will define the molecular details of a major regulatory network in the maintenance of lipid homeostasis.