Role of NgBR in Hepatic Steatosis

项目摘要 肝脏脂肪变性是发生在美国人群中最常见的新兴肝病，由 肝细胞内脂类的异常积聚。肝X受体α(LXR)是一种重要的 转录因子调节促进新生脂肪生成的基因，特别是脂肪的生物合成 脂肪酸(FAs)和甘油三酯(TGS)，这是导致肝脏脂肪变性的原因。我实验室最近的研究 提示Nogo-B受体(NGBR)在调节LXR核中起着以前未被认识的作用 易位。我们的新发现支持ngbr抑制lxr核转位的概念，并且 NGBR的表达对于防止LXR依赖的脂肪生成是必不可少的。然而，分子 NGBR调节LXR易位的机制尚不清楚。这项提议旨在 填补我们关于NGBR在调节LXR易位中的作用的知识空白，并 确定阻断LXR核转位是否足以预防肝脏脂肪变性。初步 结果表明，ngbr在脂肪肝中的表达减少，并且ngbr肝细胞特异性基因敲除。 (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LXR核移位，导致肝脏脂肪变性。基于这些发现和 以前的报道中，我们假设NGBR通过调节肝细胞LXRα核转位。 LKB1-AMPK途径，而这一调控的破坏会导致肝脏脂肪变性。我们的总体目标是 阐明NGBR阻止LXR核转位的分子机制及其作用 在肝脏脂肪变性的发病机制中起着重要作用。描述NGBR调控LXR的机制 核移位将使我们能够开发新的治疗策略来预防肝脏脂肪变性。 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。目的2：确定NGBR- LKB_1-AMPK通路调节LXRα的磷酸化和核转位。目标3：确定角色 NGBR在肝脏脂肪变性和脂肪性肝炎的发病机制中发挥作用；并确定 预防LXR核转位可改善肝脏脂肪变性。拟议的研究将揭示新的 预防和/或减少肝脏脂肪变性的治疗策略，因此对 肝病领域。如果成功，我们将是第一个展示ngbr信号如何调节分子的。 导致肝脏脂肪变性的机制。我们的研究将带来新的发现，这些发现将极大地改善 美国公民和其他患有肝脏脂肪变性的人的健康。我们的研究将揭示新的概念和 可以用来开发治疗肝脏脂肪变性的疗法的想法。因此，翻译后的 这一应用的潜力很大，与NIH的使命高度相关。

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.