Integrated Regulation of Bile Acids and Diabetes

胆汁酸与糖尿病的综合调节

• 批准号: 7225821
• 负责人: Timothy F Osborne
• 金额: $ 7.02万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7225821
• 关键词: DNA binding protein; cholanate compound; cholesterol; chromatin immunoprecipitation; cytochrome P450; disease /disorder model; genetic promoter element; genetically modified animals; heat shock proteins; laboratory mouse; lipid metabolism; noninsulin dependent diabetes mellitus; peroxisome proliferator activated receptor; protein binding; protein protein interaction; receptor binding; receptor expression; steroid metabolism; tissue /cell culture; transcription factor; transfection

DESCRIPTION (provided by applicant): Cholesterol is a critical nutrient that is required as a structural component of cell membranes and is a precursor in the biosynthesis of steroid hormones and bile acids. It is important that cholesterol levels are properly regulated because aberrant metabolism causes molecular defects in development and neurological function, and contributes to obesity, diabetes, atherosclerosis, and cancer. Thus, a fundamental understanding of cholesterol metabolism is key to mechanisms that underlie many of the major diseases of modern society. This proposal is focused on one aspect of the regulation of cholesterol, its conversion into bile acids. In preliminary studies, partly included in a recent publication, we have uncovered a novel role for the transcriptional co-activator PGC-1alpha in converting bile acids. PGC-1a is up-regulated during diabetes and fasting. A key role for PGC-1alpha in both diabetes and bile acid metabolism would provide a new link between cholesterol metabolism and diabetes. Our studies have shown that the gene for the rate controlling enzyme of the classic bile acid pathway, CYP7A1, is also up-regulated along with PGC-1alpha during fasting and in an animal model of type I diabetes. Our central hypothesis is that PGC-1alpha links bile acid metabolism with diabetes and we are evaluating the molecular mechanism for this association. Here, we plan to use both pharmacological and genetic manipulation to evaluate PGC-1alpha in regulation of CYP7A1 expression, bile acid metabolism, and hepatic glucose metabolism.

描述（由申请人提供）：胆固醇是一种关键营养素，作为细胞膜的结构成分所需，是类固醇激素和胆汁酸的生物合成的前体。重要的是要适当调节胆固醇水平，因为异常代谢会导致发育和神经功能的分子缺陷，并导致肥胖，糖尿病，动脉粥样硬化和癌症。因此，对胆固醇代谢的基本理解是基于现代社会许多主要疾病的机制的关键。 该提议的重点是调节胆固醇的一个方面，即转化为胆汁酸。在初步研究中，部分包括在最近的出版物中，我们发现了转录共激活因子PGC-1alpha在转化胆汁酸中的新作用。 PGC-1A在糖尿病和禁食期间被上调。 PGC-1Alpha在糖尿病和胆汁酸代谢中的关键作用将提供胆固醇代谢与糖尿病之间的新联系。我们的研究表明，在禁食期间和I型糖尿病的动物模型中，经典胆汁酸途径的速率控制酶的基因也与PGC-1Alpha一起上调。我们的中心假设是PGC-1Alpha将胆汁酸代谢与糖尿病联系起来，我们正在评估该关联的分子机制。在这里，我们计划使用药理和遗传操作来评估PGC-1Alpha在调节CYP7A1表达，胆汁酸代谢和肝葡萄糖代谢方面。