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新陈代谢 信号，提供最佳蛋白质储备，以满足机体的代谢和能量需求。这个 营养调控基因表达的细胞内信号通路和分子机制 才刚刚开始被拆解。这项提案的长期目标是理解一种 代谢调节：肝细胞中发生的造脂酶基因的转录诱导 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 肝脏中的葡萄糖诱导脂肪生成过程。我们以前已经定义了一个 这些基因中的几个保守的调节序列，即碳水化合物反应元件或杂务 对于这项规定来说，这是必要的，也是充分的。在过去的资助期，一种新的肝核 由转录因子ChREBP(Chore结合蛋白)和Mix(MAX样因子X)组成的复合体 已被证明能与家务结合，并调节高血糖的影响。我们假设 糖代谢增强导致ChREBP-Mix复合体的共价修饰以激活其 转录潜能。此外，我们假设ChREBP-Mix复合体是一个重要的 肝细胞中的转录调节因子，控制其他代谢途径对葡萄糖的反应。至 测试这些假说，并进一步表征葡萄糖反应转录复合体的作用 提出了以下具体目标：(1)评价CHREBP的翻译后修饰和 糖代谢变化对其修饰和活性的影响；(2)探讨糖代谢的功能 ChREBP-Mix在葡萄糖调节途径中的伙伴；(3)研究ChREBP-Mix的功能作用 在肝细胞中进行基因表达分析。这些研究应该能让我们破译信号 肝细胞“感觉”葡萄糖代谢增加的途径，并通过改变其 转录程序。鉴于ChREBP-Mix复合体在代谢转换中的关键地位 碳水化合物对脂肪的作用，它在肥胖、2型糖尿病并发症中的潜在作用，以及 “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.