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，其对美国人的身体、经济和生活造成重大影响。 情感的代价因此，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累被认为有助于T2D的发展。在 同时，脂质支持胰岛素分泌。我们的目标是了解细胞内的细胞器称为脂质 β细胞中的微滴（LD）调节脂质的双刃剑作用。我们迄今为止的工作表明， 脂滴蛋白perilipin 2和5（PLIN 2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β细胞免受营养应激。PLIN 5与脂肪甘油三酯脂肪酶相互作用 （ATGL）并支持胰岛素分泌。PLIN 2作为惰性池螯合脂质，并保护β细胞免受 脂质超载然而，β细胞不能无限期地继续积累脂质。因此，LD的途径 清除对于在营养应激下维持β细胞健康是重要的。脂肪吞噬是LD的自我消化， 溶酶体，并且已知在广泛的细胞中在LD清除中起作用。重要的是， 脂肪吞噬与肥胖脂肪细胞和脂肪肝有关。然而，人们对一个角色知之甚少， 脂肪吞噬的能力。我们的初步数据表明，在β细胞中， 没有营养缺乏。有趣的是，在INS 1细胞、大鼠胰岛和人非胰岛细胞中利帕的慢性抑制， 糖尿病胰岛损害胰岛素分泌。因此，我们假设LD的溶酶体降解是关键的， 对于β细胞的LD稳态和胰岛素分泌，以及脂肪吞噬功能的损害加速β细胞的胰岛素分泌。 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：确定利帕如何调节β细胞中的LD催化剂和脂质代谢， 常规和糖脂毒性条件：我们的初步数据表明，利帕和ATGL各自具有 在β细胞中LD动员中的独特作用。我们将阐明利帕和ATGL如何赋予空间和 使用其中利帕和ATGL下调的β细胞在LD处的脂质代谢的时间调节。 具体目标2：确定利帕在维持β细胞功能和健康方面的作用：我们的 初步数据表明，脂肪吞噬作用的长期抑制对胰岛素分泌有负面影响。我们将 解决利帕缺乏如何影响β细胞的健康和功能，在定期和glucolipotoxic条件。 具体目标3：确定脂肪吞噬功能障碍是否有助于T2D中的β细胞衰竭。它有 已经提出，在T2D的发展过程中，溶酶体在β细胞中变得功能障碍。这可能 造成利帕的功能缺陷，需要溶酶体的酸性。此外，营养压力可能 在T2D的发展过程中，通过脂肪吞噬增加对LD清除的需求。在这里，我们将测试 使用体外和体内模型研究营养应激与β细胞中的脂肪吞噬的关系。我们将 了解受损的脂肪吞噬是否有助于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.