Lipoprotein Lipase Through the Secretory System

通过分泌系统的脂蛋白脂肪酶

• 批准号: 10586798
• 负责人: Saskia Neher
• 金额: $ 38.19万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-21 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10586798
• 关键词: ADP-Ribosylation Factors; Adipocytes; Adipose tissue; Affect; Biology; Blood; Cause of Death; Caveolins; Cell Line; Cell secretion; Cell surface; Cells; Cellular biology; Circulation; Complement; Cryoelectron Microscopy; Defect; Diabetes Mellitus; Endoplasmic Reticulum; Ensure; Environment; Enzymes; GLUT 4 protein; Glucose Transporter; Golgi Apparatus; Heart Diseases; Homeostasis; Hormones; Hypertriglyceridemia; Individual; Insulin; Insulin Resistance; Intervention; Leptin; Link; Lipase; Lipids; Lipoproteins; Membrane Proteins; Microscopy; Modeling; Movement; Outcome; Oxidation-Reduction; Pathway interactions; Plasma; Polysaccharides; Process; Protein Biochemistry; Proteins; Proteomics; Quality Control; Risk Factors; Role; Secretory Vesicles; Signal Transduction; Sorting; Structure; System; Triglycerides; Type 2 diabetic; Vesicle; Work; blood lipid; cell type; diabetic; dimer; disulfide bond; experimental study; heart disease risk; high risk; inhibitor; insulin signaling; lipoprotein lipase; non-diabetic; preservation; prevent; protein kinase D; response; trafficking

Abstract: Lipoprotein lipase (LPL) reduces triglyceride levels in the blood. Elevated triglyceride levels are a risk factor for heart disease, and triglyceride levels are correlated with insulin resistance in diabetic individuals. Here, we aim to better understand an underappreciated aspect of LPL biology: most of the LPL that is synthesized never makes it out of the cell. Some of this LPL misfolds and can’t escape endoplasmic reticulum (ER) quality control. Additionally, some fully functional LPL is stored in poorly defined secretory vesicles at the periphery of the cell, and this LPL is degraded if cellular signals do not trigger its release. The ER-resident membrane protein Lipase Maturation Factor 1 (LMF1) aids in LPL folding in, and exit from, the ER. Our studies have shown that LMF1 helps to ensure LPL’s disulfide bonds are correctly processed. We don’t know the mechanism by which LMF1 aids in LPL disulfide bond processing, and in Aim 1 we will study LMF1’s structure and function. With respect to the trafficking of LPL stored in secretory vesicles, studies to date indicate that, in adipose tissue, this LPL is secreted in response to insulin signaling. However, we do not fully understand the trafficking itinerary that mobilizes stored LPL for secretion from the cell in response to insulin. In Aim 2, we will explore how vesicles containing stored LPL are selected, mobilized, and released after insulin signaling. Together, these two aims will define the factors and mechanisms that contribute to ensuring LPL’s exit from the cell to the circulation where it can lower triglycerides. Defining these mechanisms will suggest new ways to lower triglycerides and the burden of diabetes and heart disease.

摘要： 脂蛋白脂肪酶（LPL）降低血液中的甘油三酯水平。甘油三酯水平升高是一种 糖尿病患者的甘油三酯水平与胰岛素抵抗相关 个体在这里，我们的目标是更好地了解LPL生物学的一个未被充分认识的方面： 合成的LPL绝不会离开细胞。其中一些LPL错误折叠， 逃逸内质网（ER）质量控制。此外，一些功能齐全的LPL LPL储存在细胞周围的分泌囊泡中，如果 细胞信号不会触发它的释放。ER驻留膜蛋白脂肪酶成熟 因子1（LMF 1）有助于LPL折叠进入ER和从ER退出。我们的研究表明，LMF 1 有助于确保LPL的二硫键得到正确处理。我们不知道它的机制 其中LMF 1有助于LPL二硫键的加工，在目的1中，我们将研究LMF 1的结构 和功能关于储存在分泌囊泡中的LPL的运输，迄今为止的研究 表明在脂肪组织中，这种LPL是响应胰岛素信号而分泌的。但我们 我不完全了解贩运行程，调动储存的LPL分泌从 细胞对胰岛素的反应。在目标2中，我们将探索含有储存LPL的囊泡如何在细胞内形成。 在胰岛素信号传导后被选择、动员和释放。这两个目标将共同定义 有助于确保LPL从细胞退出到循环的因素和机制， 可以降低甘油三酯。明确这些机制将提出降低甘油三酯的新方法 以及糖尿病和心脏病的负担。