The Role of c-Myc in Glucose Homeostasis

描述（由申请人提供）：胰岛素允许强大的葡萄糖生成信号代谢产物，启动基因表达程序，增加肝脏利用和减少葡萄糖生成。糖尿病中断胰岛素与葡萄糖信号传导的关系，导致肝脏代谢基因表达失调；肝脏基本上处于禁食状态，无法处理丰富的细胞外代谢燃料。尽管葡萄糖信号在代谢基因的协调调节中占据主导地位，但很少有实验室致力于揭示葡萄糖作用的机制。我的实验室就是其中之一，在这里，我们采用一种新的方法来剖析葡萄糖信号传导的机制和肝脏从禁食到进食状态的表型转换。转录因子c-Myc对细胞葡萄糖代谢的调节具有强有力的控制作用，并且是在禁食结束时协调基因表达变化的候选因子。我们最近发表的初步数据表明，内源性的c-Myc水平是肝细胞中葡萄糖调节基因表达所必需的，并且c-Myc以葡萄糖依赖的方式与葡萄糖应答基因的启动子结合。综上所述，这些数据证明c-Myc在糖代谢代谢基因的协调表达中起着积极而直接的作用。我们假设c-Myc是葡萄糖介导的基因转录和肝细胞正常葡萄糖代谢所必需的，葡萄糖可以改变c-Myc的活性。特异性目的1将确定基因表达模式的改变和肝细胞中c-Myc急剧减少或增加表达的代谢后果。特异性Aim 2将确定c-Myc调节代谢基因表达的机制。本提案中概述的研究将为c-Myc协调葡萄糖调节基因表达并促进肝脏快速向摄食转变的机制提供新的见解。这些研究的长期目标是了解血糖调节基因表达的协调机制，以便开发干预措施，以规避胰岛素信号受损，改善糖尿病患者的血糖控制。

DESCRIPTION (provided by applicant): Insulin is permissive for powerful glucose-generated signaling metabolites that initiate a program of gene expression that increases hepatic utilization and decreases glucose production. Diabetes mellitus interrupts the relationship between insulin and glucose signaling, and leads to disregulated hepatic metabolic gene expression; the liver essentially becomes trapped in the fasted state, unable to process abundant extracellular metabolic fuel. Despite the predominant role of glucose signaling in the coordinated regulation of metabolic genes, very few laboratories are working to unravel the mechanisms of glucose action. My laboratory is one of these, and here we take a new approach to dissect the mechanisms of glucose signaling and the phenotypic switch of the liver as it transits from the fasted to the fed state. The transcription factor c-Myc has potent control over the regulation of cellular glucose metabolism and is a candidate for coordinating changes in gene expression that occur at the end of a fast. Our recently published and preliminary data demonstrate that endogenous levels of c-Myc are required for glucose-regulated gene expression in hepatocytes, and that c-Myc binds to the promoters of glucose-responsive genes in a glucose-dependent manner. Together, these data provide evidence that c-Myc plays an active and direct role in the coordinated expression of metabolic genes by glucose metabolism. We hypothesize that c-Myc is necessary for glucose mediated gene transcription and normal glucose metabolism in hepatocytes, and that glucose modifies c-Myc activity. Specific Aim 1 will determine the alterations in gene expression patterns and the metabolic consequences of acutely reducing or increasing expression of c-Myc in hepatocytes. Specific Aim 2 will determine the mechanisms by which c-Myc regulates metabolic gene expression. The studies outlined in the present proposal will provide new insights into the mechanisms by which c-Myc coordinates glucose regulated gene expression and promotes the fasted-to-fed transition in the liver. The long-range goal of these studies is to understand the coordinating mechanisms of glucose-regulated gene expression so that interventions may be developed to circumvent impaired insulin signaling and improve glycemic control in diabetic patients.