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: 10535520
• 负责人: Yumi Imai
• 金额: $ 49.13万
• 依托单位: UNIVERSITY OF IOWA
• 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 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10535520
• 关键词: Acid Lipase; Acidity; Acute; Address; Adipocytes; Adipose tissue; Adult; Affect; Beta Cell; Catabolism; Cell model; Cell physiology; Cells; Characteristics; Chronic; Data; Development; Diabetes Mellitus; Digestion; Emotional; Enterocytes; Exposure to; Failure; Fatty Acids; Fatty Liver; Functional disorder; Glucose; Health; Hepatocyte; Homeostasis; Human; Impairment; In Vitro; Insulin; Lead; Learning; Lipase; Lipid Mobilization; Lipids; Lipolysis; Liver; Lysosomes; Maintenance; Mediating; Metabolism; Mitochondria; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nutritional; Obesity; Organelles; Overnutrition; Pathway interactions; Physiological; Play; Process; Proteins; Rattus; Regulation; Reporting; Research; Role; Signaling Molecule; Stress; Testing; Time; Transplantation; Work; in vitro testing; in vivo; in vivo Model; insulin secretion; islet; lipid metabolism; lipid transport; negative affect; non-diabetic; novel; nutrient deprivation; perilipin; prevent; response; western diet

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.

2型糖尿病（T2D）是美国的主要健康问题 情绪高涨。因此，迫切需要有效且广泛适用的治疗。 脂质在β细胞中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。我们旨在了解细胞内细胞器如何称为脂质 β细胞中的液滴（LDS）调节脂质的双刃剑作用。迄今为止我们的工作表明 脂质液滴蛋白Peripin 2和5（PLIN2和5）在β细胞中具有独特的作用以支持胰岛素 分泌并保护β细胞免受营养应激。 PLIN5与脂肪甘油三酸酯脂肪酶相互作用 （ATGL）并支持胰岛素分泌。 PLIN2将脂质螯合为惰性池，并保护β细胞免受 脂质超负荷。但是，β细胞不能无限期地积累脂质。因此，LD的途径 清除对于在营养应激下维持β细胞健康很重要。脂肪是LDS的自消化 溶酶体且已知在广泛的细胞中在LD清除中发挥作用。重要的是，失调 寄生虫与肥胖的脂肪细胞和脂肪肝有关。但是，关于角色知之甚少 β细胞中的寄生虫。我们的初步数据表明，寄生虫在β细胞中具有组成性活性 没有营养剥夺。有趣的是，在INS1细胞，大鼠胰岛和人类非 - 慢性抑制LIPA 糖尿病胰岛会损害胰岛素分泌。因此，我们假设LDS的溶酶体降解至关重要 对于β细胞中的LD稳态和胰岛素分泌，脂肪摄氏的损害会加速β 细胞在T2D中的灭亡。以下三个目标将检验我们的假设。 特定目标1：确定LIPA如何调节β细胞下LD分解代谢和脂质代谢 常规和葡萄糖毒素条件：我们的初步数据表明LIPA和ATGL每个都有 在β细胞中LDS动员中的独特作用。我们将阐明Lipa和ATGL如何授予空间和 使用LIPA和ATGL下调的β细胞对LDS的脂质代谢的时间调节。 特定目标2：确定LIPA在维持β细胞功能和健康中的作用：我们 初步数据表明，长期抑制寄生虫会对胰岛素分泌产生负面影响。我们将 解决LIPA缺乏如何影响β细胞健康和在常规和糖毒素条件下的功能。 特定目标3：确定寄生能力障碍是否导致T2D中的β细胞衰竭。它有 被提出，在T2D发育过程中，β细胞中溶酶体的功能失调。可以 产生LIPA的功能性缺乏，需要溶酶体的酸度。另外，营养压力可能 在T2D开发过程中，脂肪噬菌对LDS清除的需求增加。在这里，我们将测试 使用体外和体内模型，β细胞中营养应激与寄生虫之间的关系。我们将 了解受损的脂肪症是否会导致T2D中的β细胞灭亡。