Role of Lipid Droplet Proteins in Islet Function in Diabetes and Obesity

脂滴蛋白在糖尿病和肥胖症胰岛功能中的作用

• 批准号: 8025355
• 负责人: Yumi Imai
• 金额: $ 31.21万
• 依托单位: EASTERN VIRGINIA MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-15 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8025355
• 关键词: Accounting; Acute; Address; Adenoviruses; Adipose tissue; Adverse effects; Area; Beta Cell; Biological Process; Capsid Proteins; Cell Line; Cell membrane; Cell surface; Cells; Ceramides; Cholesterol Homeostasis; Chronic; Data; Development; Diabetes Mellitus; Eicosanoid Production; Electron Microscopy; Enzymes; Esterification; Exposure to; Fasting; Fatty Acids; Functional disorder; Generations; Genes; Glucose; Hepatocyte; Human; In Vitro; Individual; Inflammation; Insulin; Islets of Langerhans; Knock-out; Knowledge; Laboratories; Lipids; Lipolysis; Literature; Measures; Mitochondria; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Nutritional; Obesity; Organelles; Oxidative Stress; Palmitic Acids; Pathway interactions; Play; Prevention; Process; Production; Proteins; Regulation; Role; Signal Transduction; Signaling Molecule; Stress; Surface; Testing; Transgenic Organisms; Triglyceride Metabolism; Up-Regulation; cell type; design; endocrine pancreas development; endoplasmic reticulum stress; fatty acid metabolism; feeding; in vivo; innovation; insulin secretion; islet; lipid metabolism; macrophage; novel; novel strategies; oxidation; prevent; protein expression; receptor; response; small hairpin RNA

DESCRIPTION (provided by applicant): The chronic exposure of islets to fatty acids is believed to promote the development of diabetes in obesity by damaging ? cells. Paradoxically, fatty acids also augment insulin secretion acutely. Therefore a better understanding of the regulation of lipid metabolism in islets, especially from spatial and chronological aspects, is critical for the effective strategy to prevent adverse effects of lipid overload. Adipose differentiation-related protein (ADFP), found on the surface of lipid droplets in wide range of cells, is proposed to play a critical role in spatial organization of intracellular lipid metabolism through the interaction with other intracellular organelles such as cell membrane, ER, and mitochondria. The preliminary data from Dr. Imai's laboratory showed that ADFP is increased in human and mouse islets exposed to fatty acids in vivo and ex vivo. Furthermore the reduction of ADFP in insulin secreting cells (MIN6) impairs fatty acid usage and acute augmentation of insulin secretion by fatty acids. Therefore Dr. Imai hypothesizes that ADFP coated lipid droplets in ? cells are critical for the efficient use of fatty acids. They facilitate the generation of fatty acid derived signaling for insulin secretion, while preventing islet dysfunction from lipid overload. The hypothesis will be tested as below. Specific aim 1: Analyze the role of ADFP in the acute augmentation of insulin secretion by fatty acids. The importance of ADFP in this process will be confirmed by reducing ADFP in human islets using adenovirus expressing shRNA, and in vivo using ADFP deficient mice. The mechanisms by which ADFP regulates the generation of signals for insulin secretion will be studied in mouse islets using shRNA for ADFP. Specific aim 2: Analyze the role of ADFP in the development of islet dysfunction in obesity. Since ADFP may promote fatty acid utilization in ? cells, it potentially protects islet from stress of fatty acid overload. Here the efficacy of ADFP upregulation in the prevention of lipid-induced islet dysfunction will be tested using adenovirus in vitro, and using the transgenic approach in vivo. Specific aim 3: Address the roles of islet lipid droplets beyond the regulation of fatty acids-triglycerides metabolism. Recent studies in various cells indicate that the regulatory role played by lipid droplets is not limited to fatty acid metabolism. From several areas where ADFP is implicated, two pathways relevant to islet function will be studied. The change in cholesterol metabolism and eicosanoids production will be analyzed after modulating ADFP levels in MIN6 cells and mouse islets as above. The study will provide innovative, unique information about the spatial and dynamic regulation of lipid metabolism in islets, which will aid the designing of new approaches towards the prevention and treatment of islet dysfunction commonly seen in obesity. PUBLIC HEALTH RELEVANCE: This study addresses a role of adipose differentiation-related protein in the development of islet dysfunction from lipid overload that contributes to the development of diabetes in obesity. Anticipated results will provide better understanding of the regulation of lipid metabolism in islets and will facilitate new approaches towards the prevention and treatment of type 2 diabetes.

描述（由申请人提供）：胰岛长期暴露于脂肪酸被认为会通过损害？细胞。矛盾的是，脂肪酸也会急剧增加胰岛素分泌。因此，更好地了解胰岛脂质代谢的调节，特别是从空间和时间方面，对于预防脂质超载不利影响的有效策略至关重要。脂肪分化相关蛋白（ADFP）存在于多种细胞的脂滴表面，通过与细胞膜、内质网、内质网等其他细胞器的相互作用，在细胞内脂质代谢的空间组织中发挥关键作用。和线粒体。 Imai 博士实验室的初步数据表明，在体内和离体暴露于脂肪酸的人类和小鼠胰岛中，ADFP 有所增加。此外，胰岛素分泌细胞 (MIN6) 中 ADFP 的减少会损害脂肪酸的使用和脂肪酸对胰岛素分泌的急剧增加。因此，今井博士假设 ADFP 包覆了脂滴？细胞对于有效利用脂肪酸至关重要。它们促进胰岛素分泌的脂肪酸衍生信号的产生，同时防止脂质超载引起的胰岛功能障碍。该假设将进行如下检验。具体目标 1：分析 ADFP 在脂肪酸急性增加胰岛素分泌中的作用。 ADFP 在此过程中的重要性将通过使用表达 shRNA 的腺病毒减少人类胰岛中的 ADFP 以及使用 ADFP 缺陷小鼠体内的 ADFP 来证实。将使用 ADFP 的 shRNA 在小鼠胰岛中研究 ADFP 调节胰岛素分泌信号生成的机制。具体目标 2：分析 ADFP 在肥胖症胰岛功能障碍发展中的作用。由于 ADFP 可能会促进脂肪酸的利用？细胞，它可能保护胰岛免受脂肪酸超载的压力。在此，将使用体外腺病毒和体内转基因方法测试 ADFP 上调在预防脂质诱导的胰岛功能障碍中的功效。具体目标 3：解决胰岛脂滴在脂肪酸-甘油三酯代谢调节之外的作用。最近对各种细胞的研究表明，脂滴发挥的调节作用不仅限于脂肪酸代谢。从涉及 ADFP 的几个领域，将研究与胰岛功能相关的两条途径。如上所述调节 MIN6 细胞和小鼠胰岛中的 ADFP 水平后，将分析胆固醇代谢和类二十烷酸产生的变化。 该研究将提供有关胰岛脂质代谢空间和动态调节的创新、独特信息，这将有助于设计预防和治疗肥胖症中常见的胰岛功能障碍的新方法。 公共健康相关性：本研究探讨了脂肪分化相关蛋白在脂质超载引起的胰岛功能障碍中的作用，而脂质超负荷导致肥胖症中糖尿病的发生。预期结果将有助于更好地了解胰岛脂质代谢的调节，并将促进预防和治疗 2 型糖尿病的新方法。