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.

项目摘要/摘要 脂质代谢的破坏与包括肥胖症在内的代谢综合征有关， 糖尿病和非酒精性脂肪肝病（NAFLD）。 NAFLD的特征是 肝细胞中的脂质可以发展为非酒精性脂肪性肝炎（NASH），这已经增加 肝细胞死亡，炎症和纤维化。发展和发展的分子基础 NAFLD/NASH仍然很了解。结果，这种迅速发展没有有效的治疗疗法 有健康问题。因此，该领域有明显的未满足研究的需求。肝非常低密度 脂蛋白（VLDL）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质血症。液泡膜蛋白1（VMP1）是ER 通过促进自噬体的闭合来调节自噬的膜蛋白。最近的证据 证明VMP1在脂蛋白分泌中起着至关重要的作用 培养的肝癌细胞和斑马鱼。 VMP1也是调节胆固醇稳态的ER cramblase。 本应用程序的主要目标是了解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，因为它是调查 调节NAFLD的脂质代谢和发展的新途径。在此执行的工作 应用将使NAFLD领域有关VMP1作为ER-的中心调节剂的关键作用丰富 线粒体串扰，该串扰在NAFLD发展中调节多层的VLDL分泌。我们的 奇特的前提是，VMP1的损失会损害VLDL分泌并促进NAFLD/NASH。我们的 提案得到关键初步数据的支持，包括：1）在 小鼠损害了VLDL的分泌，导致肝脂肪变性和纳什。 2）VMP1对于音乐会至关重要 - 线粒体串扰，以调节NAFLD的VLDL分泌。提出了三个具体目标：1） 确定VMP1损失降低肝磷脂酰胆碱的机制和 磷脂酰乙醇胺含量导致VLDL分泌和NASH受损； 2）破译角色和 VMP1在调节VLDL分泌，磷脂合成和自噬中的结构域； 3）确定 VMP1改善饮食诱导的VLDL分泌和NASH的机制。长期 这项工作的术语目标是确定在调节脂质代谢和的依赖VMP1的途径 NAFLD/NASH的发病机理，这可能会导致制定治疗NASH和其他的潜在策略 代谢疾病通过靶向VMP1。