INSULIN REGULATION OF G6PDH

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DESCRIPTION (Adapted from applicant's abstract): Insulin regulates the expression of many genes involved in a variety of metabolic processes. Studies aimed at understanding insulin regulation of gene expression have focused on key enzymes in glycolysis, gluconeogenesis, glycogen and fatty acid synthesis. To date, no common element that is involved in this regulation has been found. Unlike the extensive characterization that has been done on the expression of enzymes for glycolysis, gluconeogenesis, glycogen and fatty acid synthesis, little has been done with respect to the pentose phosphate pathway. This pathway can be considered to be at the interface of carbohydrate and lipid metabolism in that not only is carbohydrate metabolized but also NADPH is produced for the biosynthesis of fatty acids. In the liver, insulin, induces the synthesis of glucose-6-phosphate dehydrogenase (G6PDH), the key rate-limiting enzyme in the pentose phosphate pathway. Understanding the mechanism by which G6PDH is regulated is therefore of major importance in understanding not only the regulation of carbohydrate but also fatty acid metabolism. We hypothesize that G6PDH is an ideal model to study ho insulin can attenuate both metabolic pathways. Detailed studies of insulin regulation of the gene for this enzyme may therefore lead to a better understanding of the coordinate control of both carbohydrate and fatty acid metabolism and this is critical for our understanding of metabolic disorders such as cardiovascular disease and diabetes. As outlined in the following specific aims, the goal of this proposal is to systematically delineate and determine the mechanism by which insulin regulates the expression of G6PDH. To accomplish this, the investigators will first delineate the DNA sequences that are required for G6PDH induction by insulin. The investigators will then characterize the protein factor(s) that bind the DNA and are required for this increased expression of the gene.