SREBPs in Regulation of Lipid Metabolism

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DESCRIPTION (provided by applicant): Our research program is focused on mechanisms by which nutritional input and metabolic demand regulate genes of lipid metabolism. In mammals there are three SREBPs that are major regulators of genes in lipid metabolism. SREBP-1a and 1c are encoded by overlapping mRNAs from a single gene and SREBP-2 is transcribed from a distinct gene. SREBPs bind DMA as dimers through their bHLHLZ domains and they have the potential to homo and heterodimerize with one another. In this proposal, we evaluate the specific functions of the individual homo and heterodimers in activation of SREBP target genes by combining cell culture and animal models to obtain a multi-level perspective on lipid regulation by these complex transcription factors. In Aim 1 we engineer transformed cells that simultaneously express only two different SREBP isoforms (each under the control of a separate regulatory inducer) in order to examine the functional roles of the individual SREBP homo and heterodimers in binding to and activation of target genes. In Aim 2 we move away from artificial manipulation of the individual SREBPs and instead focus on the consequences of dietary fluctuation and pharmacologic challenge to SREBP binding and activation of target genes in a mouse model. In Aim 3 we combine the strengths of artificial manipulation of SREBPs and animal models to study mice that over-express both 1a and 1c simultaneously. This is of particular interest because it will allow us to test our hypothesis that 1c attenuates 1 a activity (based on cell culture studies) in an animal model. These studies are highly significant for two reasons: 1) understanding the function of the individual SREBPs will predict how physiologic or pharmacologic changes in their expression alter lipid metabolism in animals, 2) The human genome contains only 30,000 individual genes, so gene number is insufficient to account for the incredible complexity of an individual human being. Expression of multiple proteins from overlapping mRNAs (like SREBP-1a and -1c) and differential association of protein monomers into distinct dimers/complexes with unique functional properties (also a property of SREBPs) are two mechanisms that significantly increase genomic coding potential. Thus, the SREBP system provides a well-defined experimental model to evaluate molecular mechanisms that contribute to the expansion of genome complexity from the DNA to protein level.