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 cte novo 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 are 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. ? ?
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