Role of lipid droplet protein in obesity and diabetes

脂滴蛋白在肥胖和糖尿病中的作用

基本信息

批准号：
9240032
负责人：
Yumi Imai
金额：
$ 37.86万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-02-15 至 2021-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9240032
关键词：
Acute Address Adipose tissue Affect Agreement Alanine Autophagocytosis Beta Cell Cell Line Cell Survival Cell physiology Cell surface Cells Characteristics Cholesterol Esters Chronic Consensus Cultured Cells Cyclic AMP Cyclic AMP-Dependent Protein Kinases Data Development Diabetes Mellitus Drosophila genus Energy-Generating Resources Exocytosis Exposure to Fasting Fatty Acids Fatty acid glycerol esters Funding Generations Glucose Glutamic Acid Goals Health Hepatocyte High Fat Diet Homeostasis Human Hyperglycemia Impairment In Vitro Inflammation Insulin Knockout Mice Knowledge Lead Lipase Lipid Mobilization Lipids Lipolysis Liver Mediating Methods Molecular Molecular Profiling Molecular Target Mus Mutate Non-Insulin-Dependent Diabetes Mellitus Nutritional Obese Mice Obesity Organelles Oxidative Stress Pathogenesis Pathway interactions Pattern Pharmacology Phospholipids Phosphorylation Play Post-Translational Protein Processing Predisposition Prevention Production Protein Family Proteins Proteomics Regulation Resistance Resolution Rodent Role Serine Signal Transduction Signaling Molecule Stress Surface Testing Translating Triglycerides Up-Regulation Yeasts blood glucose regulation cytotoxicity endoplasmic reticulum stress fatty acid metabolism feeding glucagon-like peptide 1 improved in vivo inhibitor/antagonist insulin secretion islet lipid metabolism lipid transport long chain fatty acid mouse model mutant new therapeutic target non-diabetic nutrient deprivation overexpression perilipin prevent response small molecule tandem mass spectrometry

项目摘要

Lipids within cells are stored in an organelle termed lipid droplets (LDs) that consist of neutral lipids core of diacylglycerides, triglycerides, and cholesterol ester covered by a single layer of phospholipids. Recent evidence indicates a pivotal role of LD in the spatial and temporal regulation of intracellular lipid metabolism. Our project aims to understand the regulation of intracellular lipid metabolism through the study of LD in beta cells considering the critical role of lipids in beta cell. Metabolites produced by lipolysis augment insulin secretion, while unregulated accumulation of lipids impair beta cell health and leads to diabetes. The perilipin (PLIN1-5) family of proteins resides on the surface of LD and plays a key role in the formation and mobilization of LD. Our goal is to understand the mechanisms by which PLIN affects insulin secretion and to clarify the role of PLIN in the pathogenesis of abnormal lipid metabolism in beta cells under type 2 diabetes (T2D). We have demonstrated that both PLIN2 and PLIN5 are expressed in human and mouse islets, but their expression is differentially regulated. We have shown that PLIN5 plays a significant role in increasing insulin secretion likely through the regulation of lipid metabolism acutely, especially lipolysis in beta cells. PLIN2 may aid adaptation of beta cells to nutritional stress. Thus, we hypothesize that PLIN2 and 5, each with unique molecular characteristics coordinately achieve the efficient regulation of insulin secretion and protect beta cells under nutritional stress. The hypothesis will be tested by 2 aims. Specific Aim 1: Determine the mechanism by which PLIN5 augments GSIS and lipolysis. PLIN5 augments GSIS both in vitro and in vivo, which we hypothesize is mediated by lipolysis. Here, we will delineate the pathway connecting PLIN5 and GSIS. The impact of PLIN5 deficiency in beta cells on glucose homeostasis will be tested in beta cell specific PLIN5 knockout mice. The contribution of PLIN5 phosphorylation in lipid metabolism and GSIS will be tested using phosphorylation resistant mutant PLIN5 expressed in cultured cell and in beta cells of mice. Lastly, the molecular target that mediates the augmentation of PLIN5 will be determined by increase lipolysis through mutant PLIN5 and pharmacological modulation of lipolysis. Specific Aim 2: Determine how perilipins protect beta cells under nutritional stress. Studies in yeast, drosophila, and mouse liver implicate that LDs protect cells under nutritional stress. In beta cells, PLIN2 is highly expressed and increased by fatty acids. We have obtained preliminary data that the loss of PLIN2 in beta cells impair GSIS and islet adaptation to high fat feeding. We will determine the mechanism by which PLIN2 protect beta cells under nutritional stress. Also, we will analyze how islet PLINs and lipidome are altered in human islets affected by T2D. Our study holds promise to identify a new target that supports GSIS and protects beta cells under nutritional stress associated with T2D.

细胞内的脂质储存在称为脂滴（LD）的细胞器中，该细胞器由中性脂质核心组成甘油二酯、甘油三酯和胆固醇酯被单层磷脂覆盖。最近的有证据表明 LD 在细胞内脂质代谢的空间和时间调节中发挥着关键作用。我们的项目旨在通过研究 LD 来了解细胞内脂质代谢的调节考虑到脂质在 β 细胞中的关键作用。脂肪分解产生的代谢物增强胰岛素分泌，而脂质的不受控制的积累会损害β细胞的健康并导致糖尿病。这 perilipin (PLIN1-5) 家族蛋白位于 LD 表面，在 LD 的形成和形成中发挥着关键作用。 LD 的动员。我们的目标是了解 PLIN 影响胰岛素分泌的机制并阐明PLIN在2型糖尿病β细胞脂代谢异常发病机制中的作用（T2D）。我们已经证明 PLIN2 和 PLIN5 在人和小鼠胰岛中表达，但是它们的表达受到差异性调节。我们已经证明 PLIN5 在增加胰岛素分泌可能通过剧烈调节脂质代谢，尤其是β细胞的脂肪分解作用。 PLIN2 可能有助于 β 细胞适应营养压力。因此，我们假设 PLIN2 和 5，每个具有独特的分子特性，协同实现胰岛素分泌和胰岛素分泌的高效调节在营养压力下保护β细胞。该假设将通过 2 个目标进行检验。具体目标 1：确定 PLIN5 增强 GSIS 和脂肪分解的机制。 PLIN5 增强体外和体内的 GSIS，我们假设是由脂肪分解介导的。在这里，我们将描绘连接 PLIN5 和 GSIS 的通路。 β细胞中PLIN5缺陷对葡萄糖稳态的影响将在 β 细胞特异性 PLIN5 敲除小鼠中进行测试。 PLIN5 磷酸化对脂质的贡献将使用培养物中表达的磷酸化抗性突变体 PLIN5 来测试代谢和 GSIS 细胞和小鼠的β细胞中。最后，介导 PLIN5 增强的分子靶点将是通过突变 PLIN5 增加脂肪分解和脂肪分解的药理调节来确定。具体目标 2：确定周脂质如何在营养应激下保护 β 细胞。酵母研究，果蝇和小鼠肝脏表明 LD 可以在营养应激下保护细胞。在 β 细胞中，PLIN2 是脂肪酸高度表达和增加。我们已经获得初步数据表明 PLIN2 的丢失 β 细胞会损害 GSIS 和胰岛对高脂肪喂养的适应。我们将确定机制 PLIN2 在营养压力下保护 β 细胞。此外，我们还将分析胰岛 PLIN 和脂质组如何受 T2D 影响的人类胰岛发生改变。我们的研究有望确定一个支持 GSIS 并在营养条件下保护 β 细胞的新靶点与 T2D 相关的压力。