The role of fatty acid binding proteins in macrophage response to lipotoxicity

描述(申请人提供)：细胞质脂质伴侣或脂肪酸结合蛋白(FABP)，巨噬细胞和脂肪细胞常见，在肥胖相关的胰岛素抵抗和动脉粥样硬化中起核心作用。该应用的长期目标是阐明FABPs在动脉粥样硬化和糖尿病发病机制中的分子机制。我们的主要目标是描绘脂类介导的信号转导通路，介导FABPs的下游效应。在这项研究中，我们建议基于先前研究的结果来研究FABP在巨噬细胞中的作用，即巨噬细胞特异性的FABP，而不是FABP的全身效应，是导致动脉粥样硬化的主要因素。具体的假设是巨噬细胞对脂毒应激的应激反应是由FABP介导的。这是基于我们的探索性工作，揭示了脂毒应激诱导内质网应激反应需要脂肪细胞/巨噬细胞脂肪酸结合蛋白aP2。本应用的具体目的是：(1)在体内，确定脂肪酸结合蛋白在介导脂毒性相关的内质网应激反应和巨噬细胞和动脉粥样硬化病变中的凋亡中的作用。我将分析暴露于脂毒应激，通过脂肪酸或游离胆固醇负荷影响的内质网应激和细胞凋亡的诱导，FABP缺陷和FABP重组巨噬细胞。此外，我还将确定在载脂蛋白E缺乏的背景下，FABP缺陷小鼠皮损中发生的内质网应激和巨噬细胞凋亡的程度。(2)确定脂肪酸结合蛋白在脂质介导的促生存信号转导中的作用。我将分析FABP缺陷和FABP重组巨噬细胞中几个脂肪酸或胆固醇敏感信号转导通路的激活，即AMPK/mTOR/s6K1和PPAR/LXR。(3)确定PPAR和LXR在FABP缺乏引起的巨噬细胞生物学改变以及对动脉粥样硬化和胰岛素抵抗的保护作用中的作用。这一目标将通过分析FABP和PPAR或FABP和LXR双重缺陷的巨噬细胞和小鼠来实现。从这些研究中获得的机械性见解可能会导致针对肥胖相关疾病的特定治疗目标，如动脉粥样硬化和糖尿病，这些疾病是主要的公共卫生问题。

DESCRIPTION (provided by applicant): The cytoplasmic lipid chaperons or fatty acid binding proteins (FABP), common to macrophages and adipocytes, have a central role in obesity associated insulin resistance and atherosclerosis. The long-term goal of this application is to elucidate the molecular mechanisms of FABPs in the pathogenesis of atherosclerosis and diabetes. The broad objective is to delineate lipid mediated signal transduction pathways mediating the downstream effects of FABPs. In this study we propose to study FABP actions in macrophages based on the findings from previous studies that macrophage-specific FABP, and not systemic effects of FABPs, is the predominant contributor to atherosclerosis. The specific hypothesis is macrophage stress responses to lipotoxic stress are mediated by FABPs. This is based on our exploratory work which revealed induction of endoplasmic reticulum stress response by lipotoxic stress requires the adipocyte/ macrophage fatty acid binding protein, aP2. The specific aims in this application are : (1) Determine the role of fatty acid binding proteins in mediating lipotoxicity associated ER stress response and apoptosis in macrophages and in atherosclerotic lesions, in vivo. I will analyze induction of ER stress and apoptosis upon exposure lipotoxic stress, affected via fatty acid or free cholesterol loading, in FABP deficient and FABP reconstituted macrophages. Also, I will determine the extent of ER stress and macrophage apoptosis occurring in lesions in FABP deficient mice in the apoE deficient background. (2) Determine the role of fatty acid binding proteins in lipid mediated pro-survival signal transduction. I will analyze activation of several fatty acid or cholesterol sensing signal transduction pathways, namely AMPK/ mTOR/s6K1 and PPAR/LXR, in FABP deficient and FABP reconstituted macrophages. (3) Determine the contribution of PPAR and LXR to FABP deficiency associated alterations in macrophage biology and protection from atherosclerosis and insulin resistance in vivo. This aim will be achieved by analyzing macrophages and mice that are double deficient for FABP and PPAR or FABP and LXR. The mechanistic insight gained from these studies could lead to specific therapeutic targets for treatment of obesity related diseases such as atherosclerosis and diabetes, which are major public health concerns.