Role of NgBR in Hepatic Steatosis

NgBR 在肝脂肪变性中的作用

• 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
• 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' -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

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： 肝细胞内脂质异常积累。肝脏 X 受体 α (LXRα) 是一种主要的 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 酸（FA）和甘油三酯（TG），导致肝脂肪变性。我实验室的最新研究 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 易位。我们的新发现支持 NgBR 抑制 LXR 核转位的概念，并且 NgBR 表达对于防止 LXR 依赖性脂肪生成至关重要。然而，分子 NgBR 调节 LXRα 易位的机制仍不清楚。该提案旨在 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 LXRα 核易位是否足以预防肝脂肪变性。初步的 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 的减少 表达诱导 LXRα 核易位，从而导致肝脂肪变性。基于这些发现和 在之前的报道中，我们假设 NgBR 通过以下途径调节肝细胞中的 LXRα 核转位： LKB1-AMPK 通路，这种调节的破坏会导致肝脂肪变性。我们的总体目标是 阐明 NgBR 阻止 LXRα 核易位的分子机制以及 NgBR 的作用 在肝脂肪变性的发病机制中发挥作用。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。目标 1：确定 NgBR-LKB1 的作用 调节 AMPK 激活的相互作用。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：确定角色 NgBR 在肝脂肪变性和脂肪性肝炎的发病机制中发挥作用；并确定程度 防止 LXR 核易位可改善肝脂肪变性。拟议的研究将揭示新的 预防和/或减少肝脂肪变性的治疗策略，从而对 肝病学领域。如果成功，我们将第一个展示 NgBR 信号如何调节分子 驱动肝脂肪变性的机制。我们的研究将带来新的发现，从而极大地改善 美国公民和其他患有肝脂肪变性的人的健康。我们的研究将揭示新概念 可用于开发治疗肝脂肪变性的疗法的想法。因此，翻译 该应用的潜力很大，并且与 NIH 的使命高度相关。