Novel effectors of insulin action in the liver

项目概要/摘要： 2型糖尿病是一种流行性健康问题，但部分原因是对糖尿病的不完全理解。 由于潜在的机制，目前的治疗或预防选择是有限的。一个中心的悖论， 2型糖尿病的发病机制是肝脏胰岛素抵抗的选择性模式，其中胰岛素不能 抑制肝脏脂肪生成，但继续刺激脂肪生成，导致高血糖症， 高胆固醇血症虽然糖和脂质代谢的急性调节主要是通过 代谢物通量的变化和关键酶活性的变构调节， 新陈代谢需要基因转录。作为一种辅助因子，将多个转录因子连接到RNA 聚合酶II，介体复合物已合并为代谢的重要调节剂。哺乳动物 介体复合物由多达30个亚基组成。我们的中心假设是， 复合物通过以下方式整合激素和/或营养信号与代谢基因表达： 通过特异性结合结构域将相关转录因子连接到RNA聚合酶II 在特定的介体亚基中。 该提议集中于中介子亚基MED 15和GATA 4之间的新相互作用 转录因子除了我们以前的工作表明，MED 15刺激脂肪生成的共同作用， 激活SREBP-1c转录因子，我们的初步研究支持肝GATA 4/MED 15的作用， 复合物在激活胰岛素生成和胰岛素抵抗的发展中的作用。有趣的是，虽然 其分子机制尚不清楚，人类遗传学研究表明Gata 4基因突变 （可能获得的功能）在所有报告的遗传变异中， 高胆固醇血症我们的假设将在两个具体目标中进行检验：目标1将研究胰岛素调节 目的2将研究肝脏MED 15共激活的作用， SREBP-1c和GATA 4与胰岛素抵抗一种结合遗传学和基因传递的方法 将使用代谢、生物化学和分子分析来实现这些目标。所有关键动物 已建立了模型、试剂和技术，并取得了初步的支持性结果。 得到了总的来说，成功完成拟议的研究将产生一个新的见解， 这可能是选择性肝胰岛素抵抗的潜在机制，也可能有助于开发新的 2型糖尿病的干预策略。

Project Summary/Abstract: Type 2 diabetes is an epidemic health problem, but in part due to the incomplete understanding on the underlying mechanisms, the current treatments or preventive options are limited. A central paradox in the pathogenesis of type 2 diabetes is the selective mode of hepatic insulin resistance, in which insulin fails to suppress hepatic gluconeogenesis but continues to stimulate lipogenesis, resulting in hyperglycemia and hypertriglyceridemia. Although the acute regulation of glucose and lipid metabolism is largely through changes in metabolite flux and allosteric modulation of key enzyme activities, the chronic regulation of metabolism requires gene transcription. As a cofactor that links multiple transcription factors to RNA polymerase II, the Mediator complex has merged as an important regulator of metabolism. The mammalian Mediator complex is composed of up to 30 subunits. Our central hypothesis is that the Mediator complex integrates hormonal and/or nutritional signals with metabolic gene expression by connecting relevant transcription factors to RNA polymerase II through specific binding domains within particular Mediator subunits. This proposal is focused on a novel interaction between the Mediator subunit MED15 and GATA4 transcription factor. In addition to our previous work showing that MED15 stimulates lipogenesis by co- activating SREBP-1c transcription factor, our preliminary studies support a role of hepatic GATA4/MED15 complex in activating gluconeogenesis and in the development of insulin resistance. Interestingly, although the molecular mechanisms are unknown, human genetic studies indicate that mutations in Gata4 gene (likely gain of function) among all reported genetic variations display the strongest correlation with hypertriglyceridemia. Our hypothesis will be tested in two Specific Aims: Aim 1 will study insulin regulation of hepatic GATA4 in glucose metabolism, and Aim 2 will study the role of hepatic MED15 coactivating SREBP-1c and GATA4 in insulin resistance. A combined genetic and gene delivery approaches together with metabolic, biochemical and molecular analyses will be used to carry out these Aims. All key animal models, reagents and techniques have been established, and supportive preliminary results have been obtained. Overall, successful completion of the proposed studies will yield a novel insight into the mechanisms underlying selective hepatic insulin resistance, and may also aid the development of novel interventional strategies against type 2 diabetes.