Role of NgBR in Hepatic Steatosis

项目摘要 肝脂肪变性是美国人群中最常见的新发肝病，由以下原因引起： 肝细胞内脂质的异常积累。肝脏X受体α（LXR α）是一种主要的 用于调节促进从头脂肪生成，特别是脂肪酸生物合成的基因的转录因子 脂肪酸（FA）和甘油三酯（TG），这有助于肝脂肪变性。我实验室最近的研究 表明Nogo-B受体（NgBR）在调节LXR核转录中起着以前未认识到作用， 易位我们的新发现支持了NgBR抑制LXR受体核转位的概念， NgBR表达对于防止LXR受体依赖性脂肪生成至关重要。然而，分子 NgBR调节LXR易位的机制仍然未知。这项建议旨在 填补了我们关于NgBR在调节LXR β易位中作用的知识空白， 确定阻断LXR β核转位是否足以预防肝脂肪变性。初步 结果显示，NgBR表达在脂肪肝中降低，NgBR肝细胞特异性敲除 （hepKO）小鼠肝脏中的FA和TG含量增加。这些数据表明， 表达诱导LXR β核转位，这导致肝脂肪变性。根据这些发现， 在先前的报道中，我们假设NgBR通过调节LXR α在肝细胞中的核转位， LKB1-AMPK通路，这种调节的破坏导致肝脂肪变性。我们的总体目标是 阐明NgBR阻止LXR γ核转位的分子机制，以及NgBR在LXR γ核转位中的作用。 在肝脂肪变性的发病机制中起作用。描述NgBR调节LXR的机制 核转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。目的1：确定NgBR-LKB 1的作用 相互作用调节AMPK活化。目的2：确定NgBR- LKB1-AMPK通路调节LXR α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起作用;并确定其在多大程度上 阻止LXR β核转位可改善肝脂肪变性。这些研究将揭示新的 预防和/或减少肝脂肪变性的治疗策略， 肝脏病学领域。如果成功的话，我们将是第一个展示NgBR信号如何调节分子水平的人。 驱动肝脂肪变性的机制我们的研究将导致新的发现，这将大大改善 健康的美国公民和其他患有脂肪肝。我们的研究将揭示新的概念， 这些想法可用于开发治疗肝脂肪变性的疗法。因此，平移 这种应用的潜力是强大的，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.