Novel effectors of insulin action in the liver

项目摘要/摘要： 2型糖尿病是一个流行性的健康问题，但部分原因是对 在根本机制方面，目前的治疗或预防选择是有限的。一个核心的悖论在 2型糖尿病的发病机制是肝脏胰岛素抵抗的选择性模式，在这种模式下胰岛素不能 抑制肝脏糖异生，但继续刺激脂肪生成，导致高血糖和 高甘油三酯血症。虽然糖和脂代谢的急性调节主要是通过 代谢产物通量的变化和关键酶活性的变构调节，慢性调节 新陈代谢需要基因转录。作为一种将多个转录因子连接到RNA的辅因子 聚合酶II，介体复合体已合并为重要的新陈代谢调节因子。哺乳动物 介体复合体由多达30个亚基组成。我们的中心假设是调解人 Complex通过以下方式将激素和/或营养信号与代谢基因表达相结合 通过特定结合域将相关转录因子连接到RNA聚合酶II 在特定的介体亚基内。 这项建议的重点是介体亚单位MED15和GATA4之间的一种新的相互作用 转录因子。除了我们之前的工作表明，MED15通过共同促进脂肪生成 激活SREBP-1c转录因子，我们的初步研究支持肝脏GATA4/MED15的作用 在激活糖异生和胰岛素抵抗的发展过程中具有复杂的作用。有趣的是，尽管 其分子机制尚不清楚，人类遗传学研究表明，Gata4基因突变 (可能的功能获得)在所有已报道的遗传变异中，与 高甘油三酯血症。我们的假设将在两个特定的目标中得到检验：目标1将研究胰岛素的调节 肝脏GATA4在葡萄糖代谢中的作用，目标2将研究肝脏MED15共激活的作用 SREBP-1c和GATA4在胰岛素抵抗中的作用一种结合遗传和基因传递的方法 代谢、生化和分子分析将用于实现这些目标。所有关键动物 已经建立了模型、试剂和技术，并取得了支持性的初步结果 获得。总括而言，建议研究的成功完成，将使我们对 选择性肝脏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.