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.

抽象的： 脂蛋白脂肪酶 (LPL) 会降低血液中的甘油三酯水平。 心脏病的危险因素，甘油三酯水平与糖尿病患者的胰岛素抵抗相关 在这里，我们的目标是更好地了解 LPL 生物学中一个未被充分重视的方面：大多数。 合成的 LPL 永远不会从细胞中排出，其中一些 LPL 会错误折叠，无法从细胞中排出。 此外，一些功能齐全的 LPL 是逃逸内质网 (ER) 质量控制的。 储存在细胞外围的不明确的分泌囊泡中，并且如果 细胞信号不会触发内质网驻留膜蛋白脂肪酶的释放。 因子 1 (LMF1) 有助于 LPL 折叠并退出 ER 我们的研究表明，LMF1。 有助于确保 LPL 的二硫键得到正确处理，但我们不知道其机制。 LMF1 有助于 LPL 二硫键加工，在目标 1 中我们将研究 LMF1 的结构 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。 不完全了解调动储存的 LPL 进行分泌的贩运行程 在目标 2 中，我们将探讨含有储存的 LPL 的囊泡是如何产生的。 在胰岛素信号传导后选择、动员和释放，这两个目标将共同定义。 影响LPL退出的因素和机制确保从细胞到循环 它可以降低甘油三酯，定义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。