PGC-1beta in the Regulation of Hepatic Lipid Metabolism

描述(申请人提供)：代谢综合征正在成为一种全球流行病。这种综合征的严重代谢紊乱典型地表现为几种疾病的聚集，包括肥胖、2型糖尿病和血脂异常，并与心血管疾病的风险增加有关。肝脏的脂肪生成和脂蛋白代谢是维持脂质平衡的重要因素。越来越多的证据表明，肝脂代谢在代谢综合征的关键环节，包括高脂血症、高血糖和胰岛素抵抗的发病机制中起着重要作用。我们最近证明了转录共激活因子PGC-1？协调调节肝脏中的脂肪生成、脂肪运输和脂蛋白代谢。这些数据提示PGC-1？是维持脂质动态平衡的调控网络的中心组成部分。这项提议的主要目标是检验PGC-1？参与代谢综合征的发病机制，是脂代谢和胰岛素抵抗之间的分子纽带。此外，PGC-1？将对路径进行解剖和分析。目的1确定评价PGC-1的作用？在代谢紊乱的发病机制中，以及将脂代谢与胰岛素抵抗联系起来。目标2是定义PGC-1的转录成分？甘油三酯和脂蛋白代谢的调节。目的3探讨染色质重塑在脂质代谢中的作用。这项提案的完成将确定维持脂质稳态的主要调控网络的分子细节。

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.