Role of Fatty Acid Binding Proteins in Lipid Signaling

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DESCRIPTION (provided by applicant): It is likely that a FA binding protein (FABP) will regulate FA-sensitive intracellular signaling pathways involved in the pathogenesis of Metabolic Syndrome. We have reported two FABP-deficient mouse models, aP2-/- and mal1-/-, that are protected from developing obesity-induced insulin resistance and atherosclerosis to varying degrees, aP2 and mal1 are highly expressed in the macrophage, a cell important in the formation of atheroscterosic lesions. In the absence of aP2, macrophages have alterations in FA and cholesterol metabolism. The hypothesis is that FABPs will modify macrophage lipid biology. This proposal aims to further characterize the direct mechanism of FABP action in macrophage biology. First, lipid metabolism will be investigated in established single (aP2 or mal1) and double (aP2/mal1) -/- macrophage cell lines. Second, the cholesterol metabolic pathway will be studied in these cell lines. Third, inhibitors to proteins central to the cholesterol efflux pathway, namely PPARgamma, will be used in wildtype and FABP null macrophage cell lines to demonstrate at which point in the pathway FABPs are acting. Ultimately, FABP-deficient mice will be crossed into mice deficient for one of these candidate proteins to examine primary macrophage biology, and the formation of atherosclerosis.