Role of NgBR in Hepatic Steatosis

NgBR 在肝脂肪变性中的作用

基本信息

批准号：
9981481
负责人：
QING MIAO
金额：
$ 41.98万
依托单位：
NYU WINTHROP HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9981481
关键词：
5&apos -AMP-activated protein kinase Attenuated Automobile Driving Binding Cell Nucleus Cell Surface Receptors Cell membrane Cell surface Cholesterol Complement Cytoplasm Cytoplasmic Tail Data Disease FASN gene Fatty Acids Fatty Liver Genes Genetic Genetic Transcription Goals Health Hepatic Hepatocyte Hepatology High Fat Diet Human Hydrophobicity Impairment Intervention Knockout Mice Knowledge LXRalpha protein Laboratories Lead Ligands Link Lipids Liver Liver diseases Mediating Membrane Mission Molecular Nuclear Nuclear Receptors Nuclear Translocation Pathogenesis Pathway interactions Phosphorylation Play Population Protein Kinase Receptor Signaling Regulation Reporting Research Role STK11 gene Signal Transduction Signaling Molecule Steatohepatitis Testing Triglycerides United States National Institutes of Health base design disability fatty acid biosynthesis improved lipid biosynthesis novel novel strategies novel therapeutic intervention oxidation prevent receptor receptor binding receptor expression success therapeutic target therapy development transcription factor

项目摘要

Project Summary Hepatic steatosis is the most common emerging liver disease occurring in the US population, and is caused by an abnormal accumulation of lipids within hepatocytes. The Liver X receptor alpha (LXR) is a major transcription factor for regulating the genes promoting de novo lipogenesis, specifically biosynthesis of fatty acids (FAs) and triglycerides (TGs), which contributes to hepatic steatosis. Recent studies from my laboratory suggest that Nogo-B receptor (NgBR) plays a previously unrecognized role in regulating LXRnuclear translocation. Our new findings support the concept that NgBR inhibits nuclear translocation of LXR and that NgBR expression is essential for preventing LXRdependent lipogenesis. However, the molecular mechanisms by which NgBR regulates LXR translocation remain unknown. This proposal is designed to fill gaps in our knowledge concerning the role of NgBR in regulating LXR translocation, and to determine if blocking LXR nuclear translocation is sufficient to prevent hepatic steatosis. Preliminary results show that NgBR expression is decreased in fatty livers, and NgBR hepatocyte-specific knockout (hepKO) mice have increased FA and TG content in the liver. These data suggest that a decrease in NgBR expression induces LXR nuclear translocation, which lead to hepatic steatosis. Based on these findings and previous reports, we hypothesize that NgBR regulates LXRα nuclear translocation in hepatocytes through the LKB1-AMPK pathway, and disruption of this regulation leads to hepatic steatosis. Our overall objectives are to elucidate the molecular mechanisms by which NgBR prevents LXR nuclear translocation and the roles NgBR plays in the pathogenesis of hepatic steatosis. Delineating the mechanisms by which NgBR regulates LXR nuclear translocation will allow us to develop new therapeutic strategies for preventing hepatic steatosis. Accordingly, we will test our hypothesis in the three specific aims. Aim 1: Determine the roles of NgBR-LKB1 interaction in regulating AMPK activation. Aim 2: Determine the molecular mechanism by which the NgBR- LKB1-AMPK pathway regulates LXRα phosphorylation and nuclear translocation. Aim 3: Determine the roles NgBR plays in the pathogenesis of hepatic steatosis and steatohepatitis; and, determine the extent to which preventing LXR nuclear translocation ameliorates hepatic steatosis. The proposed studies will reveal new therapeutic strategies for preventing and/or reducing hepatic steatosis and thus have a significant impact on the field of hepatology. If successful, we will be the first to show how NgBR signaling regulates the molecular mechanisms driving hepatic steatosis. Our studies will lead to new discoveries that will greatly improve the health of US citizens and others suffering from hepatic steatosis. Our studies will reveal new concepts and ideas that can be used to develop therapies for treating hepatic steatosis. Accordingly, the translational potential of this application is strong and highly relevant to NIH's mission.

项目概要肝脂肪变性是美国人群中最常见的新出现的肝脏疾病，由以下原因引起：肝细胞内脂质的异常积累是一个主要因素。用于调节促进从头脂肪生成，特别是脂肪生物合成的基因的转录因子我实验室最近的研究表明，脂肪酸（FA）和甘油三酯（TG）会导致肝脂肪变性。表明 Nogo-B 受体 (NgBR) 在调节 LXR核中发挥着以前未被认识到的作用我们的新发现支持 NgBR 抑制 LXR 核易位的概念，并且 NgBR 表达对于 LXR 依赖性脂肪生成至关重要，然而，它阻止了分子的发生。 NgBR 调节 LXR 易位的机制仍然未知。该提案的目的是。填补了我们关于 NgBR 在调节 LXR 易位中的作用的知识空白，并确定阻断 LXR 核易位是否足以预防肝脂肪变性。结果显示脂肪肝中NgBR表达降低，NgBR肝细胞特异性敲除 (hepKO) 小鼠肝脏中 FA 和 TG 含量增加，这些数据表明 NgBR 减少。根据这些发现，表达会诱导 LXRα 核易位，从而导致肝脂肪变性。在之前的报道中，我们研究了NgBR通过以下途径调节肝细胞中的LXRα核转位： LKB1-AMPK 通路，破坏该调节会导致肝脂肪变性。阐明 NgBR 阻止 LXRα 核易位的分子机制以及 NgBR 的作用描述 NgBR 调节 LXR 的机制。核易位将使我们能够开发新的治疗策略来预防肝脂肪变性。因此，我们将在三个具体目标中检验我们的假设：确定 NgBR-LKB1 的作用。目标 2：确定 NgBR- 的分子机制。 LKB1-AMPK 通路调节 LXRα 磷酸化和核转位目标 3：确定作用。 NgBR 在肝脏脂肪变性和脂肪性肝炎的发病机制中发挥作用，并决定其程度；防止 LXR 核易位可改善肝脂肪变性。拟议的研究将揭示新的内容。预防和/或减少肝脂肪变性的治疗策略，从而对如果成功，我们将第一个展示 NgBR 信号如何调节分子。我们的研究将带来新的发现，从而极大地改善肝脂肪变性。我们的研究将揭示美国公民和其他患有肝脂肪变性的人的健康状况。因此，可用于开发治疗肝脂肪变性的疗法的想法。该应用潜力巨大，并且与 NIH 的使命高度相关。