Mechanisms regulating lipoprotein secretion and lipid metabolism

项目摘要/摘要 脂代谢紊乱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的特点是积累了 肝细胞中的脂质可进展为非酒精性脂肪性肝炎(NASH)，后者已增加 肝细胞死亡、炎症和纤维化。肿瘤发生发展的分子基础研究进展 NAFLD/NASH仍然知之甚少。因此，没有有效的治疗方法来治疗这种迅速增长的疾病 健康问题是可用的。因此，这一领域显然存在尚未得到满足的研究需求。肝脏极低密度 脂蛋白(VLDL)的分泌在调节肝内和血管内脂类平衡方面是必不可少的。受损的 极低密度脂蛋白的分泌导致肝脏脂肪变性和低脂血症。液泡膜蛋白1(VMP1)是一种内质网 通过促进自噬小体的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，而不依赖于其自噬功能。 培养的肝癌细胞和斑马鱼。VMP1也是一种内质网扰乱酶，调节胆固醇动态平衡。 本应用程序的主要目标是了解VMP1通过 调节脂肪代谢和非酒精性脂肪肝的进展。我们的建议意义重大，因为它是为了调查 调节脂代谢与非酒精性脂肪肝发生的新途径。在此项下执行的工作 应用将丰富NAFLD领域关于VMP1作为ER-1的中央调节因子的关键作用。 线粒体串扰，在NAFLD的发展过程中调节多层VLDL的分泌。我们的 科学的前提是VMP1的缺失会损害VLDL的分泌，促进NAFLD/NASH的发生。我们的 主要的初步数据支持这一建议，包括：1)VMP1在肝细胞中的特异性缺失 2)VMP1在内质网中起关键作用。 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缺失降低肝脏磷脂酰胆碱和 磷脂酰乙醇胺含量导致VLDL分泌受损和NASH；2)破译其作用和 VMP1在调节极低密度脂蛋白分泌、磷脂合成和自噬中的结构域；以及3)决定 VMP1改善饮食诱导的VLDL分泌受损和NASH的机制。长的- 这项工作的长期目标是确定VMP1依赖的调节脂质代谢的途径和 NAFLD/NASH的发病机制可能导致开发治疗NASH和其他疾病的潜在策略 通过靶向VMP1治疗代谢性疾病。

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.