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

脂肪酸结合蛋白在巨噬细胞脂毒性反应中的作用

• 批准号: 7333408
• 负责人: Ebru Erbay
• 金额: $ 5.13万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7333408
• 关键词: Activation Analysis; Address; Adipocytes; Adipose tissue; Affect; Apolipoprotein E; Apoptosis; Arterial Fatty Streak; Atherosclerosis; Biology; Cardiovascular Diseases; Cell Line; Cholesterol; Development; Diabetes Mellitus; Disease; Dyslipidemias; Employee Strikes; Endoplasmic Reticulum; Fatty Acids; Genetic Models; Goals; Homeostasis; Human; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Insulin; Insulin Resistance; Knowledge; Lead; Lesion; Link; Lipids; Mails; Mediating; Mediator of activation protein; Metabolic; Metabolic syndrome; Metabolism; Molecular; Molecular Chaperones; Mus; Obesity; Obesity associated disease; Pathogenesis; Pathology; Pathway interactions; Peroxisome Proliferator-Activated Receptors; Phenotype; Play; Protein Deficiency; Public Health; Regulation; Role; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Site; Stress; Testing; Work; atherogenesis; base; biological adaptation to stress; diabetes risk; fatty acid binding protein; fatty acid-binding proteins; genetic variant; human FRAP1 protein; in vivo; in vivo Model; insight; lipid metabolism; macrophage; mouse model; reconstitution; response; therapeutic target

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.

描述（由申请人提供）：巨噬细胞和脂肪细胞常见的细胞质脂质伴侣或脂肪酸结合蛋白（FABP）在肥胖相关胰岛素抵抗和动脉粥样硬化中起核心作用。本申请的长期目标是阐明FABPs在动脉粥样硬化和糖尿病发病机制中的分子机制。广泛的目标是描绘脂质介导的信号转导途径介导的下游影响的脂肪酸结合蛋白。在这项研究中，我们建议研究脂肪酸结合蛋白在巨噬细胞的行动的基础上，从以前的研究发现，巨噬细胞特异性脂肪酸结合蛋白，而不是全身的影响，脂肪酸结合蛋白，是动脉粥样硬化的主要贡献者。具体的假设是巨噬细胞对脂毒性应激的应激反应是由FABPs介导的。这是基于我们的探索性工作，其揭示了脂毒性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aP 2。本申请的具体目的是：（1）确定脂肪酸结合蛋白在体内介导巨噬细胞和动脉粥样硬化病变中的脂毒性相关的ER应激反应和凋亡中的作用。我将分析在FABP缺陷和FABP重建的巨噬细胞中，通过脂肪酸或游离胆固醇负荷影响暴露脂毒性应激后ER应激和细胞凋亡的诱导。此外，我将确定ER应激和巨噬细胞凋亡的程度发生在病变的FABP缺陷小鼠在apoE缺陷的背景。(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。我将分析几个脂肪酸或胆固醇传感信号转导途径，即AMPK/ mTOR/s6 K1和PPAR/LXR，在FABP缺陷和FABP重建的巨噬细胞的激活。(3)确定体内PPAR和LXR对FABP缺乏相关的巨噬细胞生物学改变的贡献，以及对动脉粥样硬化和胰岛素抵抗的保护作用。这一目标将通过分析FABP和PPAR或FABP和LXR双缺陷的巨噬细胞和小鼠来实现。从这些研究中获得的机制见解可能导致用于治疗肥胖相关疾病如动脉粥样硬化和糖尿病的特定治疗靶点，这些疾病是主要的公共卫生问题。