The Role of c-Myc in Glucose Homeostasis

描述(申请人提供)：胰岛素允许产生强大的葡萄糖信号代谢产物，启动基因表达程序，增加肝脏利用率，减少葡萄糖产生。糖尿病干扰了胰岛素和葡萄糖信号转导的关系，导致肝脏代谢基因表达失调，肝脏基本上陷入禁食状态，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控中起着主要作用，但很少有实验室致力于解开葡萄糖作用的机制。我的实验室就是其中之一，在这里，我们采取了一种新的方法来剖析葡萄糖信号的机制和肝脏从禁食状态到饲料状态的表型转换。转录因子c-Myc对细胞葡萄糖代谢的调节有很强的控制力，是协调禁食结束时基因表达变化的候选基因。我们最近发表的初步数据表明，c-Myc的内源性水平是葡萄糖调节的基因表达所必需的，并且c-Myc以葡萄糖依赖的方式与葡萄糖反应基因的启动子结合。综上所述，这些数据为c-Myc通过葡萄糖代谢在代谢基因的协调表达中发挥积极而直接的作用提供了证据。我们假设c-Myc对于葡萄糖介导的基因转录和肝细胞内正常的葡萄糖代谢是必需的，并且葡萄糖可以改变c-Myc的活性。具体目标1将确定c-Myc在肝细胞中表达急剧减少或增加所引起的基因表达模式的改变和代谢后果。特异性目标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协调葡萄糖调节的基因表达和促进肝脏从禁食到喂养过渡的机制提供新的见解。这些研究的长期目标是了解葡萄糖调节基因表达的协调机制，以便开发干预措施来绕过受损的胰岛素信号，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.