Role of lipid droplet protein in obesity and diabetes

细胞内的脂类储存在一个称为脂滴(LDS)的细胞器中，它由中性脂类组成，其核心是 由单层磷脂覆盖的甘油二酯、甘油三酯和胆固醇酯。近期 有证据表明，LD在细胞内脂代谢的时空调节中起着关键作用。 我们的项目旨在通过对LD的研究来了解细胞内脂代谢的调节。 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加胰岛素 分泌，而无节制的脂质积累损害了β细胞的健康，并导致糖尿病。这个 Perilipin(PLIN1-5)家族蛋白位于LD表面，在LD的形成和形成过程中起关键作用。 动员LD。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在人和小鼠的胰岛中都有表达，但是 它们的表达受到不同的调控。我们已经证明，PLIN5在增加 胰岛素的分泌很可能是通过调节脂肪代谢，尤其是β细胞中的脂解作用。 Plin2可能有助于β细胞适应营养压力。因此，我们假设PLIN2和PLIN5各自 具有独特的分子特性，协同实现胰岛素分泌的有效调节和 在营养压力下保护贝塔细胞。这一假设将通过两个目标进行检验。 具体目标1：确定PLIN5增强GSIS和脂解作用的机制。PLIN5增强版 GSIS在体外和体内都存在，我们推测它是由脂解作用介导的。在这里，我们将描述 连接PLIN5和GSIS的通路。胰岛β细胞PLIN5缺乏对血糖稳态的影响 将在贝塔细胞特异性PLIN5基因敲除小鼠身上进行测试。PLIN5磷酸化在脂质中的作用 代谢和GSIS将使用在培养的细胞中表达的磷酸化抗性突变体PLIN5进行测试 细胞和小鼠的β细胞中。最后，介导PLIN5增强的分子靶点将是 由通过突变的PLIN5增加脂解作用和药物调节脂解作用而确定。 具体目标2：确定Perilipins如何在营养压力下保护β细胞。对酵母的研究， 果蝇和小鼠的肝脏表明，LDS在营养压力下保护细胞。在β细胞中，PLIN2是 高表达，并由脂肪酸增加。我们已经获得了初步数据，PLIN2的丢失在 β细胞损害GSIS和胰岛对高脂肪喂养的适应。我们将确定通过什么机制 Plin2在营养压力下保护β细胞。此外，我们还将分析胰岛绒毛和脂肪乳突是如何 受T2D影响的人的胰岛发生了改变。 我们的研究有望找到一种新的靶点，支持GSIS并在营养条件下保护β细胞 与T2D相关的应力。

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.