Role of lipid droplet proteins in islet function in diabetes and obesity

2型糖尿病(T2D)是美国的主要健康问题，给人们带来了巨大的身体、经济和 情感上的过路费。因此，迫切需要一种有效且广泛适用的治疗方法。 β细胞中脂质的过度积聚被认为是导致T2D的原因之一。在 同时，脂质支持胰岛素的分泌。我们的目标是了解细胞内细胞器是如何被称为脂质的 β细胞中的液滴(LDs)调节脂质的双刃剑作用。到目前为止，我们的工作表明 脂滴蛋白Perilipin 2和5(PLIN2和5)各自在β细胞中具有支持胰岛素的独特作用 分泌和保护贝塔细胞免受营养压力。PLIN5与脂肪甘油三酯脂肪酶相互作用 (ATGL)，并支持胰岛素分泌。Plin2以惰性池的形式隔离脂类，保护β细胞免受 脂质过载。然而，β细胞不能无限期地持续积累脂质。因此，学习困难的一条途径 清除对维持营养压力下的β细胞健康很重要。吞脂症是LDS的自我消化。 溶酶体和已知在广泛的细胞中起清除LD的作用。重要的是，监管失调 吞脂性与肥胖的脂肪细胞和脂肪肝有关。然而，对于角色，人们知之甚少。 在β细胞中的吞脂性。我们的初步数据显示，吞脂性在β细胞中具有结构性活性。 而不会被剥夺营养。有趣的是，LIPA在INS1细胞、大鼠胰岛和人类非淋巴细胞中的慢性抑制作用 糖尿病胰岛损害胰岛素的分泌。因此，我们假设LDS的溶酶体降解是至关重要的。 对于LD稳态和β细胞中胰岛素的分泌，以及脂噬功能的障碍加速β细胞 T2D中的细胞死亡。以下三个目标将检验我们的假设。 具体目标1：确定LIPA如何调节β细胞的LD分解代谢和脂代谢 正常和糖毒性条件：我们的初步数据表明，LIPA和ATGL各自有一个 在β细胞中动员LDS的独特作用。我们将阐明LIPA和ATGL如何授予空间和 LIPA和ATGL下调的β细胞对LDS脂代谢的时间调节。 具体目标2：确定LIPA在维持β细胞功能和健康中的作用 初步数据表明，长期抑制脂噬作用会对胰岛素分泌产生负面影响。我们会 阐述LIPA缺乏如何在正常和糖毒性条件下影响β细胞的健康和功能。 具体目标3：确定吞脂功能障碍是否导致T2D中的β细胞衰竭。它有 有人提出，在T2D的发育过程中，溶酶体在β细胞中功能失调。这可能会 造成LIPA的功能性缺陷，需要溶酶体的酸性。此外，营养压力可能会 在T2D的开发过程中，通过吞脂清除LDS的需求增加。在这里，我们将测试 用体外和体内模型研究营养应激与β细胞吞脂性的关系。我们会 了解吞脂功能受损是否导致T2D中的β细胞死亡。

Type 2 diabetes (T2D) is the major health problem in the US that imposes significant physical, financial, and emotional tolls. Thus, there is a strong and urgent need for an effective and widely applicable therapy. Excessive accumulation of lipids in beta cells is considered to contribute to the development of T2D. At the same time, lipids supports insulin secretion. We aim to understand how an intracellular organelle termed lipid droplets (LDs) in beta cells regulate a double-edged sword action of lipids. Our work to date has shown that lipid droplet protein perilipin 2 and 5 (PLIN2 and 5) each has a unique role in beta cells to support insulin secretion and protects beta cells from nutritional stress. PLIN5 interacts with adipose triglycerides lipase (ATGL) and supports insulin secretion. PLIN2 sequestrates lipids as an inert pool and protects beta cells from lipid overload. However, beta cells cannot continue to accumulate lipids indefinitely. Thus, a pathway of LD clearance is important to maintain beta cell health under nutritional stress. Lipophagy is self-digestion of LDs at lysosome and known to play a role in LD clearance in a wide range of cells. Importantly, dysregulation of lipophagy has been associated with obese adipocytes and fatty liver. However, little is known regarding a role of lipophagy in beta cells. Our preliminary data showed that lipophagy is constitutively active in beta cells without nutrient deprivation. Interestingly, chronic suppression of LIPA in INS1 cells, rat islets, and human non- diabetic islets impairs insulin secretion. Therefore, we hypothesize that lysosomal degradation of LDs is critical for LD homeostasis and insulin secretion in beta cells, and that the impairment in lipophagy accelerates beta cell demise in T2D. The following three aims will test our hypothesis. Specific Aim 1: Determine how LIPA regulates LD catabolism and lipid metabolism in beta cells under regular and glucolipotoxic conditions: Our preliminary data indicates that LIPA and ATGL each has a distinct role in mobilization of LDs in beta cells. We will clarify how LIPA and ATGL confer the spatial and temporal regulation of lipid metabolism at LDs using beta cells in which LIPA and ATGL are down-regulated. Specific Aim 2: Determine a role of LIPA in the maintenance of beta cell function and health: Our preliminary data indicates that prolonged suppression of lipophagy negatively affects insulin secretion. We will address how LIPA deficiency affect beta cell health and function at regular and glucolipotoxic conditions. Specific Aim 3: Determine whether lipophagy dysfunction contributes to beta cell failure in T2D. It has been proposed that lysosome becomes dysfunctional in beta cells during the development of T2D. This could create functional deficiency of LIPA that requires the acidity of lysosome. In addition, nutritional stress may increase demand for clearance of LDs by lipophagy during the development of T2D. Here, we will test the relationship between nutritional stress and lipophagy in beta cells using in vitro and in vivo models. We will learn whether impaired lipophagy contributes to beta cell demise in T2D.