Integrated Regulation of Bile Acids and Diabetes

描述（由申请人提供）：胆固醇是一种重要的营养素，是细胞膜的结构成分，是类固醇激素和胆汁酸生物合成的前体。胆固醇水平得到适当调节是很重要的，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现代社会许多重大疾病的基础机制的关键。 这项建议集中在胆固醇调节的一个方面，即胆固醇转化为胆汁酸。在初步研究中，部分包括在最近的出版物中，我们发现了转录辅激活因子PGC-1 α在转化胆汁酸中的新作用。PGC-1a在糖尿病和禁食期间上调。PGC-1 α在糖尿病和胆汁酸代谢中的关键作用将为胆固醇代谢和糖尿病之间提供新的联系。我们的研究表明，在禁食期间和I型糖尿病动物模型中，经典胆汁酸途径的速率控制酶CYP 7A 1的基因也与PGC-1 α一起沿着上调。我们的中心假设是PGC-1 α将胆汁酸代谢与糖尿病联系起来，我们正在评估这种联系的分子机制。在这里，我们计划使用药理学和遗传操作来评估PGC-1 α对CYP 7A 1表达、胆汁酸代谢和肝脏葡萄糖代谢的调节作用。

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.