Role of Fatty Acid Binding Proteins in Lipid Signaling

描述（由申请人提供）：FA结合蛋白（FABP）很可能会调节参与代谢综合征发病机制的FA敏感性细胞内信号通路。我们已经报道了两种FABP缺陷的小鼠模型，aP 2-/-和mal 1-/-，它们在不同程度上被保护免于发展肥胖诱导的胰岛素抵抗和动脉粥样硬化。aP 2和mal 1在巨噬细胞中高度表达，巨噬细胞是在动脉粥样硬化病变形成中重要的细胞。在缺乏aP 2的情况下，巨噬细胞具有FA和胆固醇代谢的改变。假设是FABPs将改变巨噬细胞脂质生物学。该建议旨在进一步表征FABP在巨噬细胞生物学中作用的直接机制。首先，将在已建立的单（aP 2或mal 1）和双（aP 2/mal 1）-/-巨噬细胞系中研究脂质代谢。其次，将在这些细胞系中研究胆固醇代谢途径。第三，将在野生型和FABP无效巨噬细胞系中使用胆固醇流出途径中心蛋白质的抑制剂，即PPARgamma，以证明FABP在途径中的哪个点起作用。最终，FABP缺陷小鼠将与这些候选蛋白之一缺陷的小鼠杂交，以检查初级巨噬细胞生物学和动脉粥样硬化的形成。

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.