Role of Fatty Acid Binding Proteins in Lipid Signaling

描述(申请人提供)：一种FA结合蛋白(FABP)可能会调节FA敏感的细胞内信号通路，涉及代谢综合征的发病机制。我们已经报道了两个FABP缺陷的小鼠模型，aP2-/-和Mal1-/-，它们不同程度地防止了肥胖诱导的胰岛素抵抗和动脉粥样硬化的发生，aP2和Mal1在巨噬细胞中高表达，巨噬细胞是形成动脉粥样硬化病变的重要细胞。在缺乏aP2的情况下，巨噬细胞的脂肪酸和胆固醇代谢会发生变化。假说是FABPs会改变巨噬细胞的脂质生物学。这项建议旨在进一步表征FABP在巨噬细胞生物学中的直接作用机制。首先，将研究已建立的单个(aP2或mar1)和双(aP2/mar1)-/-巨噬细胞系的脂质代谢。其次，将在这些细胞系中研究胆固醇代谢途径。第三，胆固醇外流途径中心蛋白的抑制剂，即PPARGamma，将用于野生型和FABP缺失的巨噬细胞系，以证明FABP在途径的哪个点起作用。最终，FABP基因缺陷的小鼠将被杂交到缺乏这些候选蛋白之一的小鼠中，以检测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.