Fatty Acid Binding Proteins in Macrophage Function

描述(申请人提供)：脂肪酸结合蛋白(FABP)作为各种疏水配体的细胞内受体，被认为在脂质运输中发挥作用，使疏水化合物能够输送到负责新陈代谢和细胞内信号的酶系统。最近的研究突显了FABP的重要性，在这些研究中，脂肪细胞脂肪酸结合蛋白(AP2)表达不足的基因工程小鼠被发现对肥胖引起的糖尿病和动脉粥样硬化都显示出深刻的保护作用。巨噬细胞表达高水平的aP2和角质形成细胞脂肪酸结合蛋白(MAL-1)。AP2和MAL-1是FABP，已被证明与包括环氧合酶和脂氧合酶代谢产物在内的多个已知的过氧化物酶体增殖物激活受体(PPAR)的配体结合。PPAR家族成员在巨噬细胞基因表达调控中发挥着重要作用。这一建议验证了FABP控制PPAR配体的可用性，从而影响巨噬细胞基因表达和功能的假设。已经设计了区分FABP在PPAR配体的隔离和PPAR配体的合成中的作用的实验。将评估PPAR活性，并将分析野生型和FABP缺陷巨噬细胞中已知受PPAR调控的转录因子的活性。到目前为止收集的数据表明，FABP作为促炎活性的积极调节因子，表明FABP的缺失可能在自身免疫性炎症性疾病中起到保护作用。使用实验性自身免疫性脑脊髓炎(EAE)多发性硬化症小鼠模型的初步数据支持了这一概念。这一模型将被用来提供一种手段来分析FABP在体内的功能，在这种自身免疫性炎症反应中，巨噬细胞的促炎活性已被证明是疾病进展的关键。这些研究可能会揭示一种独特的方法来调节巨噬细胞的功能，以达到治疗目的。

DESCRIPTION (provided by applicant): Fatty acid binding proteins (FABPs) act as intracellular receptors for a variety of hydrophobic ligands and are believed to play a role in lipid transport, enabling delivery of hydrophobic compounds to enzyme systems responsible for metabolism and intracellular signaling. The importance of FABPs has been underscored by recent studies in which genetically engineered mice deficient in expression of adipocyte fatty acid binding protein (aP2) were found to display profound protection from both obesity-induced diabetes and atherosclerosis. Macrophages express high levels of aP2 and keratinocyte fatty acid binding protein (mal-1). AP2 and mal-1 are FABPs which have been demonstrated to bind several identified ligands for the peroxisome proliferator-activated receptors (PPARs) which include metabolites of cyclooxygenase and lipoxygenase. PPAR family members have been demonstrated to play an important role in the regulation of gene expression in macrophages. This proposal tests the hypothesis that FABPs control the availability of PPAR ligands, thus impacting macrophage gene expression and function. Experiments have been designed which distinguish between a role of FABPs in sequestration of PPAR ligands versus the synthesis of PPAR ligands. PPAR activity will be assessed, and the activity of transcription factors known to be regulated by PPARs will be analyzed in wild-type and FABP-deficient macrophages. Data collected thus far indicate that FABPs act as positive regulators of pro-inflammatory activity, suggesting that absence of FABPs may be protective in autoimmune inflammatory disease. This concept is supported by preliminary data using the experimental autoimmune encephalomyelitis (EAE) murine model of multiple sclerosis. This model will be employed to provide a means to analyze FABP function, in vivo, in an autoimmune inflammatory response in which macrophage pro-inflammatory activity has been shown to be key to the progression of disease. These studies may reveal a unique means of modulating macrophage function for therapeutic purposes.