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.

项目总结/摘要 脂质代谢的破坏与包括肥胖在内的代谢综合征有关， 糖尿病和非酒精性脂肪肝（NAFLD）。NAFLD的特征是 肝细胞中的脂质可进展为非酒精性脂肪性肝炎（NASH）， 肝细胞死亡、炎症和纤维化。发展和进步的分子基础 NAFLD/NASH仍然知之甚少。因此，没有有效的治疗方法，这种新兴的 存在健康问题。因此，这一领域的研究需求显然没有得到满足。肝极低密度 脂蛋白（VLDL）分泌在调节肝内和血管内脂质稳态中是必需的。受损 VLDL分泌导致肝脂肪变性和低脂血症。内质网膜蛋白1（VMP 1）是一种内质网蛋白， 通过促进自噬体的闭合来调节自噬的膜蛋白。最近的证据 表明，在脂蛋白分泌中，VMP 1起着关键作用，与其自噬功能无关， 培养的肝癌细胞和斑马鱼。VMP 1也是调节胆固醇稳态的ER扰乱酶。 本应用程序的主要任务是了解VMP 1 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。在此框架下开展的工作 应用将丰富NAFLD领域关于VMP 1作为ER的中央调节器的关键作用， 线粒体串扰，其在NAFLD的发展中在多层调节VLDL分泌。我们 重要的前提是，VMP 1的缺失会损害VLDL分泌并促进NAFLD/NASH。我们 关键的初步数据支持了这一提议，包括：1）肝细胞特异性缺失VMP 1， 小鼠VLDL分泌受损，导致肝脂肪变性和NASH;和2）VMP 1对协调ER-1和ER-2的表达至关重要。 线粒体串扰调节NAFLD中VLDL分泌。提出三个具体目标：1） 确定VMP 1的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）解读磷脂酰乙醇胺的作用， VMP 1在调节VLDL分泌、磷脂合成和自噬中的结构域;和3）确定 VMP 1改善饮食诱导的VLDL分泌受损和NASH的机制。长- 这项工作的目标是确定在调节脂质代谢中的VMP 1依赖性途径， NAFLD/NASH的发病机制，这可能导致开发治疗NASH和其他疾病的潜在策略。 代谢性疾病的治疗。