Lipid Binding Proteins in Obesity and Diabetes Syndromes

肥胖和糖尿病综合征中的脂质结合蛋白

• 批准号: 8637053
• 负责人: David A Bernlohr
• 金额: $ 33.32万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-08-12 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8637053
• 关键词: Adipocytes; Adipose tissue; Adult; Anabolism; Animal Model; Asthma; Attenuated; Binding; Binding Proteins; Biology; CCL2 gene; Cardiovascular Diseases; Cell Culture Techniques; Cell Line; Characteristics; Cytokine Signaling; Development; Diabetes Mellitus; Diet; Eicosanoids; Enzymes; Exhibits; Fatty Acids; Fatty acid glycerol esters; Forskolin; Gene Expression; Genetic Polymorphism; Health; Heart Hypertrophy; Human; Human Biology; Hyperlipidemia; Hypersensitivity; Hypertension; Hypertriglyceridemia; Inflammation; Inflammatory; Insulin; Insulin Resistance; Investigation; Knockout Mice; Laboratories; Lead; Leukotriene A4; Leukotriene B4; Leukotriene C4; Leukotriene D4; Leukotriene E4; Leukotrienes; Link; Lipid Binding; Lipids; Lipolysis; Mediating; Metabolic Diseases; Metabolic syndrome; Metabolism; Modeling; Molecular; Monounsaturated Fatty Acids; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Obesity; Overweight; Pathology; Peroxisome Proliferator-Activated Receptors; Phosphorylation; Physiological; Play; Predisposition; Process; Production; Proto-Oncogene Proteins c-akt; Risk; Role; Saturated Fatty Acids; Second Messenger Systems; Sum; Surveys; Syndrome; TNF gene; Testing; Thrombosis; United States; United States National Institutes of Health; Visceral; Work; adiponectin; cysteinyl-leukotriene; cytokine; endothelial dysfunction; fatty acid-binding proteins; glucose transport; improved; insulin sensitivity; insulin signaling; macrophage; molecular site; monocyte; mouse model; promoter; receptor; second messenger

DESCRIPTION (provided by applicant): Fatty acid binding proteins (FABPS) are intracellular free fatty acid receptors found expressed at high levels in adipocytes and macrophages. FABPs bind a variety of unesterified fatty acids and other lipid second messengers and mediate their intracellular metabolism. When placed on high fat diets, FABP knockout mice exhibit attenuated characteristics of the metabolic syndrome including diminished adipocyte lipolysis, reduced TNF¿ and increased adiponectin expression, improved insulin sensitivity, decreased NF-?B activation, protection from asthma and diminished atherogenic capacity. In contrast, mice over-expressing FABP in adipose tissue exhibit potentiated characteristics of the metabolic syndrome included increased lipolysis, exacerbated insulin resistance, decreased adiponectin secretion, and mild cardiac hypertrophy. Humans with decreased adipocyte FABP (arising via a polymorphism in the AFABP/aP2 promoter) exhibit reduced risk for hypertriglyceridemia, type 2 diabetes and cardiovascular disease. In work carried out under NIH DK053189 we have demonstrated that the FABPs of adipose tissue are required for inflammatory leukotriene biosynthesis. Since LTA4 is a precursor to the monocyte recruitment factor LTB4 and the inflammatory cysteinyl leukotrienes (LTC4, LTD4 and LTE4), adipose tissue from FABP null mice and FABP null macrophage cell lines exhibit reduced levels of inflammatory eicosanoids. Treatment of macrophages with leukotrienes results in an increase in iNOS and MCP1 expression while decreasing PPAR?. Moreover, LTC4 treatment of adipocytes results in decreased phosphorylation of Akt and attenuated glucose transport while increasing basal and forskolin-stimulated lipolysis. These findings lead to the hypothesis that: fatty acids, either fro diet or from adipocyte lipolysis, stimulate resident macrophages resulting in fatty acid binding protein-dependent leukotriene synthesis. LTB4 and LTC4 promote inflammatory gene expression and cytokine secretion by macrophages, and LTC4 impairs insulin signaling, alters adipokine secretion and increases lipolysis in adipocytes. To test this hypothesis, we propose the following four specific aims: 1. Determine the role of fatty acids and fatty acid binding proteins in macrophage leukotriene biosynthesis using cell culture models. 2. Assess the role of fatty acids and fatty acid binding proteins in adipose tissue leukotriene biosynthesis using animal models. 3. Evaluate the interaction of FABPs with LTA4 and LTA4 metabolizing enzymes. 4. Examine the effects of leukotrienes on macrophage and adipocyte signal transduction and cytokine synthesis.

描述（由申请人提供）：脂肪酸结合蛋白（FABPS）是在脂肪细胞和巨噬细胞中高水平表达的细胞内游离脂肪酸受体。FABP结合多种未酯化脂肪酸和其他脂质第二信使并介导它们的细胞内代谢。当置于高脂饮食，FABP基因敲除小鼠表现出代谢综合征的衰减特征，包括减少脂肪细胞脂解，减少TNF？和增加脂联素表达，改善胰岛素敏感性，减少NF-？B活化、预防哮喘和降低致动脉粥样硬化能力。相反，脂肪组织中过表达FABP的小鼠表现出代谢综合征的增强特征，包括脂解增加、胰岛素抵抗加剧、脂联素分泌减少和轻度心脏肥大。脂肪细胞FABP降低（通过AFABP/aP 2启动子的多态性引起）的人表现出高脂血症、2型糖尿病和心血管疾病的风险降低。在NIH DK 053189下进行的工作中，我们已经证明脂肪组织的FABP是炎症性白三烯生物合成所需的。由于LTA 4是单核细胞募集因子LTB 4和炎性半胱氨酰白三烯（LTC 4、LTD 4和LTE 4）的前体，因此来自FABP缺失小鼠和FABP缺失巨噬细胞系的脂肪组织显示炎性类花生酸水平降低。用白三烯处理巨噬细胞导致iNOS和MCP 1表达增加，同时减少PPAR？。此外，LTC 4处理脂肪细胞导致Akt磷酸化降低和葡萄糖转运减弱，同时增加基础和毛喉素刺激的脂解。这些发现导致以下假设：来自饮食或脂肪细胞脂解的脂肪酸刺激常驻巨噬细胞，导致脂肪酸结合蛋白依赖性白三烯合成。LTB 4和LTC 4促进巨噬细胞的炎性基因表达和细胞因子分泌，LTC 4损害胰岛素信号传导，改变脂肪因子分泌并增加脂肪细胞中的脂解。为了验证这一假设，我们提出了以下四个具体目标：1。用细胞培养模型确定脂肪酸和脂肪酸结合蛋白在巨噬细胞白三烯生物合成中的作用。2.使用动物模型评估脂肪酸和脂肪酸结合蛋白在脂肪组织白三烯生物合成中的作用。3.评价FABP与LTA 4和LTA 4代谢酶的相互作用。4.检查白细胞三烯对巨噬细胞和脂肪细胞信号传导和细胞因子合成的影响。