Role of Hepatic RNA Silencing in Insulin Resistance and Obesity

项目摘要/摘要 生活方式和饮食趋势的急剧变化引发了一场快速的全球慢性新陈代谢流行病 疾病包括2型糖尿病(T2D)和非酒精性脂肪性肝病(NAFLD/脂肪变性)。需要 对T2D和代谢性疾病进行更有效的治疗从未像现在这样紧迫。 这项建议调查了创新的假设，即T2D是由放松管制的 肝精氨酸蛋白2(Ago2)，RNA诱导沉默复合体(RISC)的主要成分。我们的小说 初步数据表明，肝脏Ago2在调节线粒体功能方面发挥着核心作用。 T2D的发病机制。在哺乳动物中，有四种ArgAerte家族蛋白在RNA中发挥关键作用 沉默。其中，Ago2具有独特的核酸内切酶活性，对细菌的生物发生起关键作用。 特异的miRNAs和对mRNA的切割。在肝脏Ago2缺乏状态下，miRNAs的表达 已知会损害葡萄糖新陈代谢，但选择性地被抑制，而mRNAs则增强 线粒体功能增强。耐人寻味的是，我们的初步结果表明，二甲双胍治疗 诱导与其核酸内切酶活性相关的Ago2功能变化。这些初步数据表明 肝脏Ago2在调节血糖稳态中的独特和关键作用，使我们假设 AGO2通过miRNA的生物合成和RNA沉默来调节肝脏中的葡萄糖和脂肪代谢 影响线粒体功能。此外，我们假设增加Ago2介导的RNA沉默有助于 改善肝脏脂肪变性和胰岛素抵抗，降低Ago2功能可能是其治疗作用的机制之一。 二甲双胍。 本提案中的研究将：(1)确定在T2D中重要的Ago2内切酶活性 机制；(2)剖析Ago2在二甲双胍改善糖代谢中的作用 在T2D中；(3)在T2D和二甲双胍中描述对血糖控制至关重要的Ago2依赖的mRNA沉默 行动。 这项应用的目的是从机制上清楚地了解肝脏Ago2- MiRNA轴在T2D的发病机制和治疗中的作用该计划的长期目标是确定 T2D的新预防和治疗策略。

Project Summary/Abstract Drastic changes in lifestyle and dietary trends have triggered a rapid, worldwide epidemic of chronic metabolic diseases including type 2 diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD/steatosis). The need for more effective treatments of T2D and metabolic diseases has never been more urgent. This proposal investigates the innovative hypothesis that T2D results from deregulated function of hepatic Argonaute 2 (Ago2), a main component of the RNA-induced silencing complex (RISC). Our novel preliminary data indicates hepatic Ago2 plays a central role in regulating mitochondrial function in the pathogenesis of T2D. In mammals, there are four Argonaute family proteins that play crucial roles in RNA silencing. Among them, Ago2 uniquely possesses endonuclease activity that is critical for the biogenesis of specific miRNAs and for mRNA cleavage. In the hepatic Ago2-deficient state, expressions of miRNAs, which are known to impair glucose metabolism, are selectively suppressed, whereas mRNAs enhancing mitochondrial function are increased. Intriguingly, our preliminary results identified that metformin treatment induces Ago2 functional changes associated with its endonuclease activity. These preliminary data suggest unique and pivotal roles for hepatic Ago2 in regulating glucose homeostasis, leading us to hypothesize that Ago2 regulates glucose and lipid metabolism in the liver through miRNA biogenesis and RNA silencing that affects mitochondrial function. Further, we hypothesize that increased Ago2-mediated RNA silencing contribute to hepatic steatosis and insulin resistance, and decreased Ago2 function mediates the therapeutic effect of metformin. Studies in this proposal will: (1) determine the Ago2 endonuclease activity important in T2D pathogenesis; (2) dissect Ago2 function in the therapeutic effect of metformin for improved glucose metabolism in T2D; (3) delineate Ago2-dependent mRNA silencing critical in glycemic control in T2D and in metformin's action. The goal of this application is to gain a clear mechanistic understanding of the role of the hepatic Ago2- miRNA axis in the pathogenesis and in the treatment of T2D. The long-term goal of this program is to identify novel preventive and therapeutic strategies for T2D.