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

基本信息

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
项目类别：
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

项目摘要

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，对身体、经济和健康造成重大影响。情感损失。因此，迫切需要一种有效且广泛适用的疗法。 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细胞器如何被称为脂质 β细胞中的液滴（LD）调节脂质的双刃剑作用。迄今为止我们的工作表明脂滴蛋白 perilipin 2 和 5（PLIN2 和 5）在 β 细胞中各自具有支持胰岛素的独特作用分泌并保护β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 将脂质作为惰性池隔离，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压力下维持 β 细胞健康非常重要。脂噬是 LD 的自我消化溶酶体已知在多种细胞中的 LD 清除中发挥作用。重要的是，失调脂肪吞噬与肥胖脂肪细胞和脂肪肝有关。然而，人们对角色知之甚少 β细胞中的脂噬作用。我们的初步数据表明，脂肪自噬在 β 细胞中具有组成型活性不缺乏营养。有趣的是，在 INS1 细胞、大鼠胰岛和人类非细胞中长期抑制 LIPA 糖尿病胰岛会损害胰岛素分泌。因此，我们假设 LD 的溶酶体降解至关重要 LD 稳态和 β 细胞中的胰岛素分泌，并且脂噬损伤会加速 β 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 如何在条件下调节 β 细胞中的 LD 分解代谢和脂质代谢常规和糖脂毒性条件：我们的初步数据表明 LIPA 和 ATGL 各自具有在 β 细胞中 LD 的动员中发挥着独特的作用。我们将阐明 LIPA 和 ATGL 如何赋予空间和使用 LIPA 和 ATGL 下调的 β 细胞对 LD 的脂质代谢进行时间调节。具体目标 2：确定 LIPA 在维持 β 细胞功能和健康中的作用：我们的初步数据表明，长期抑制脂肪吞噬会对胰岛素分泌产生负面影响。我们将解决 LIPA 缺乏如何影响正常和糖脂毒性条件下 β 细胞的健康和功能。具体目标 3：确定自噬功能障碍是否会导致 T2D 中的 β 细胞衰竭。它有有人提出，在 T2D 的发展过程中，β 细胞中的溶酶体会出现功能障碍。这可以造成 LIPA 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，增加了通过脂肪吞噬清除 LD 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细胞中的脂肪吞噬之间的关系。我们将了解受损的脂肪吞噬是否会导致 T2D 中的 β 细胞死亡。