CONTROL OF LIPOGENIC ENZYMES BIOSYNTHESIS IN 3T3-L1 CELL

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The overall goal of this research program is to determine the molecular basis for the regulation of the biosynthesis of several lipogenic enzymes. The amounts of these enzymes are markedly altered in liver and fat cells in three fundamentally important states: (a) expression of cell differentiation and developmental programs; (b) regulation of target-cell metabolism and function by the hormones insulin, T3, epinephrine and glucagon; and (c) in a dietary paradigm involving a period of starvation followed by refeeding with a high carbohydrate/low fat diet. Three enzymes, ATP-citrate lyase (ACL), malic enzyme (ME) and glycerol 3-phosphate dehydrogenase (GPD) have been chosen for study. They are representative examples of enzymes in the direct saturated fatty acid synthesis pathway, a set of essential NADPH producting enzymes and the enzymic linkage between glycolytic and lipogenic pathways, respectively. These enzymes are members of a limited group of functionally related moderate to low abundance enzyme proteins that are often (but not always) regulated in a coordinate manner in many variations of the physiologically important states described above. Little is currently known about the molecular mechanisms underlying this coordinate control. Therefore, studies on the transcriptional and post-transcriptional regulation of these genes, the determination of the structure of coding and non-coding regions of ACL, ME and GPD genes and ultimately, the characterization of specific regulatory sequences in regions flanking the genes will provide new information and insights on processes involved in mammalian cell differentiation and the phenomena which direct target cells to coordinately reset their levels of a family of enzymes in response to hormones and nutrients. Studies will be performed on murine 3T3-L1 preadipocytes and