Nutritional and Hormonal Regulation of Hepatic Genes

哺乳动物调节其遗传信息的表达，以响应营养和代谢 信号，提供最佳的蛋白质库，以满足生物体的代谢和能量需求。的 参与营养调控基因表达的细胞内信号通路和分子机制 才刚刚开始被揭开本建议的长期目标是了解一个系统， 代谢调节：在肝细胞中发生的脂肪生成酶基因的转录诱导， 对葡萄糖代谢增加的反应。至少有16种基因产物直接或间接参与了 新生脂肪生成的过程响应于肝脏中的葡萄糖而被诱导。我们之前定义了一个 这些基因中的几个中的保守调节序列，碳水化合物反应元件或ChoRE， 这是必要的，也是充分的。在过去的资助期间，一种新的肝细胞核 由转录因子ChREBP（ChoRE结合蛋白）和Mix（Max样因子X）组成的复合物 已显示与ChoRE结合并介导葡萄糖升高的作用。我们假设 增加的葡萄糖代谢导致ChREBP-Mix复合物的共价修饰，以激活其 转录潜能此外，我们假设ChREBP-MIX复合物是一个重要的 肝细胞中的转录调节因子，其控制响应葡萄糖的其他代谢途径。到 测试这些假设，并进一步表征葡萄糖响应性转录复合物的作用， 本研究的主要目的是：（1）研究ChREBP的翻译后修饰， 探讨糖代谢变化对葡萄糖修饰和活性的影响;（2）探讨葡萄糖代谢变化对葡萄糖修饰和活性的影响。 ChREBP伴侣Mix在葡萄糖调节通路中的作用;（3）研究ChREBP-Mix的功能作用 在肝细胞中通过基因表达分析。这些研究应该能让我们破译 肝细胞可以“感知”葡萄糖代谢增加并通过改变其 转录程序鉴于ChREBP-MIX复合物在代谢转化中的关键位置， 碳水化合物转化为脂质，其在导致肥胖症、2型糖尿病和 “代谢综合征”具有重要的生物医学意义。

Mammals regulate the expression of their genetic information in response to nutritional and metabolic signals, providing the optimal protein repertoire to meet metabolic and energy needs of the organism. The intracellular signaling pathways and molecular mechanisms involved in nutrient control of gene expression are only beginning to be unraveled. The long-range goal of this proposal is to understand one system of metabolic regulation: the transcriptional induction of lipogenic enzyme genes that occurs in the hepatocyte in response to increased glucose metabolism. At least 16 gene products involved directly or indirectly in the process of ctenovo lipogenesis are induced in response to glucose in the liver. We have previously defined a conserved regulatory sequence, the carbohydrate response element or ChoRE, in several of these genes that is necessary and sufficient for this regulation. In the past funding period, a novel hepatic nuclear complex composed of the transcription factors ChREBP (ChoRE-Binding Protein) and Mix (Max-like factor X) has been shown to bind to the ChoRE and mediate the effects of elevated glucose. We hypothesize that increased glucose metabolism leads to the covalent modification of the ChREBP-Mix complex to activate its transcriptional potential. Furthermore, we hypothesize that the ChREBP-MIx complex is an important transcriptional regulator in the hepatocyte that controls other metabolic pathways in response to glucose. To test these hypotheses and further characterize the role of the glucose-responsive transcription complex, the following specific aims are proposed: (1) to evaluate the post-translational modification of ChREBP and the effect of changes in glucose metabolism on its modification and activity; (2) to explore the function of the ChREBP partner, Mix, in the glucose regulatory pathway; (3) to examine the functional roles of ChREBP-MIx in hepatocytes by gene expression analysis. These studies should allow us to decipher the signaling pathway by which the hepatocyte can 'sense' increased glucose metabolism and respond by changing its transcriptional program. Given the critical position of the ChREBP-MIx complex in the metabolic conversion of carbohydrate to lipid, its potential role in contributing to the complications of obesity, type 2 diabetes, and the 'metabolic syndrome' is of significant biomedical relevance.