Mechanisms regulating lipoprotein secretion and lipid metabolism

脂蛋白分泌和脂质代谢的调节机制

• 批准号: 10564280
• 负责人: Hongmin Ni
• 金额: $ 40.96万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10564280
• 关键词: 2019-nCoV; Area; Autophagocytosis; Autophagosome; Biogenesis; Cells; Cessation of life; Cholesterol; Cholesterol Homeostasis; Coronavirus Infections; Data; Development; Diabetes Mellitus; Diet; Disease Progression; Drosophila genus; Dyslipidemias; Endoplasmic Reticulum; Fatty Liver; Fibrosis; Goals; Health; Hepatic; Hepatocyte; High Fat Diet; Homeostasis; Human Genome; Impairment; Inflammation; Integral Membrane Protein; Intestines; Knock-in Mouse; Knockout Mice; Knowledge; Lecithin; Lipids; Lipoproteins; Liver; Liver diseases; Mediating; Membrane; Membrane Proteins; Metabolic Diseases; Metabolic syndrome; Mitochondria; Molecular; Mus; Obesity; Organelles; Outcome; Pathogenesis; Pathway interactions; Phosphatidylethanolamine; Phosphatidylserines; Phospholipids; Physiological; Play; Prevention; Protein Biosynthesis; Protein Secretion; Research; Role; Site; Vacuole; Very low density lipoprotein; Work; Zebrafish; genome wide association study; hepatoma cell; hypolipidemia; intrahepatic; lipid metabolism; mutant; new therapeutic target; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; novel therapeutic intervention; overexpression; phospholipid scramblase; prevent; restoration; therapeutically effective

Project Summary/Abstract Disruption of lipid metabolism has been associated with metabolic syndrome including obesity, diabetes and nonalcoholic fatty liver disease (NAFLD). NAFLD is characterized by the accumulation of lipids in hepatocytes that can progress to nonalcoholic steatohepatitis (NASH), which has increased hepatocyte death, inflammation and fibrosis. The molecular basis of the development and progression of NAFLD/NASH are still poorly understood. As a result, no effective therapeutic treatments for this burgeoning health problem are available. Thus, there is a clear unmet research need in this area. Hepatic very-low-density lipoprotein (VLDL) secretion is essential in regulating intrahepatic and intravascular lipid homeostasis. Impaired VLDL secretion leads to hepatic steatosis and hypolipidemia. Vacuole membrane protein 1 (VMP1) is an ER membrane protein that regulates autophagy by promoting the closure of autophagosomes. Recent evidence demonstrates that VMP1 plays a critical role in lipoprotein secretion independent of its autophagy function in cultured hepatoma cells and zebrafish. VMP1 is also an ER scramblase to regulate cholesterol homeostasis. The major OBJECTIVES of this application are to understand the role and mechanisms by which VMP1 regulates lipid metabolism and NAFLD progression. Our proposal is SIGNIFICANT because it is to investigate a novel pathway in regulating lipid metabolism and development of NAFLD. Work performed under this application will enrich the NAFLD field regarding the critical role of VMP1 as a central regulator of ER- mitochondria crosstalk, which regulate VLDL secretion at multilayers in the development of NAFLD. Our SICENTIFIC PREMISE is that loss of VMP1 impairs VLDL secretion and promotes NAFLD/NASH. Our proposal is supported by KEY PRELIMINARY DATA including: 1) Hepatocyte-specific deletion of VMP1 in mice impaired VLDL secretion resulting in hepatic steatosis and NASH; and 2) VMP1 is critical to concert ER- mitochondria crosstalk to regulate VLDL secretion in NAFLD. Three SPECIFIC AIMS are proposed: 1) Determine the mechanisms by which loss of VMP1 decreases hepatic phosphatidylcholine and phosphatidylethanolamine content resulting in impaired VLDL secretion and NASH; 2) Decipher the role and the domains of VMP1 in regulating VLDL secretion, phospholipid synthesis and autophagy; and 3) Determine the mechanisms by which VMP1 ameliorates diet-induced impaired VLDL secretion and NASH. The LONG- TERM GOAL of this work is to identify VMP1-dependent pathways in regulating lipid metabolism and the pathogenesis of NAFLD/NASH, which may lead to develop potential strategies for treating NASH and other metabolic diseases by targeting VMP1.

项目概要/摘要 脂质代谢的破坏与代谢综合征有关，包括肥胖、 糖尿病和非酒精性脂肪肝（NAFLD）。 NAFLD 的特点是积累 肝细胞中的脂质可能会发展为非酒精性脂肪性肝炎 (NASH)，这种疾病会增加 肝细胞死亡、炎症和纤维化。发育和进展的分子基础 NAFLD/NASH 人们仍然知之甚少。因此，对于这种新兴的疾病，没有有效的治疗方法 健康问题是可用的。因此，该领域显然存在未满足的研究需求。肝脏极低密度 脂蛋白（VLDL）的分泌对于调节肝内和血管内脂质稳态至关重要。受损 VLDL分泌导致肝脂肪变性和低脂血症。液泡膜蛋白 1 (VMP1) 是一种 ER 通过促进自噬体关闭来调节自噬的膜蛋白。最近的证据 表明 VMP1 在脂蛋白分泌中发挥着关键作用，独立于其自噬功能 培养的肝癌细胞和斑马鱼。 VMP1 也是一种 ER 扰乱酶，可调节胆固醇稳态。 本申请的主要目标是了解 VMP1 的作用和机制 调节脂质代谢和 NAFLD 进展。我们的建议很重要，因为它是为了调查 调节脂质代谢和 NAFLD 发展的新途径。在此下进行的工作 VMP1作为ER-的中央调节剂的关键作用的应用将丰富NAFLD领域 线粒体串扰，在 NAFLD 的发展过程中多层调节 VLDL 分泌。我们的 科学前提是 VMP1 缺失会损害 VLDL 分泌并促进 NAFLD/NASH。我们的 该提案得到了关键初步数据的支持，包括：1) 肝细胞特异性删除 VMP1 小鼠 VLDL 分泌受损，导致肝脂肪变性和 NASH； 2) VMP1 对于音乐会 ER 至关重要- 线粒体串扰调节 NAFLD 中 VLDL 的分泌。提出了三个具体目标：1) 确定 VMP1 缺失降​​低肝磷脂酰胆碱的机制 磷脂酰乙醇胺含量导致 VLDL 分泌受损和 NASH； 2) 解读角色和 VMP1 的结构域调节 VLDL 分泌、磷脂合成和自噬； 3) 确定 VMP1 改善饮食引起的 VLDL 分泌受损和 NASH 的机制。长- 这项工作的术语目标是确定调节脂质代谢的 VMP1 依赖性途径以及 NAFLD/NASH 的发病机制，这可能会导致开发治疗 NASH 和其他疾病的潜在策略 靶向VMP1的代谢性疾病。