The Unfolded Protein Response in Fatty Liver

项目摘要 非酒精性脂肪性肝病(NAFLD)是导致肝功能异常的最常见原因 在美国，是肝硬变、肝细胞癌和死亡的主要原因。虽然脂肪肝 疾病与代谢综合征有关，其发病机制尚不清楚。在 在肝脏中，蛋白质折叠的保真度是不完美的，因此过量的错误折叠或未折叠的蛋白质可能 堆积，一种称为内质网应激的情况。未折叠蛋白反应(UPR)是一种保护性信号 反应存在于所有真核细胞中，人类和动物研究表明UPR在 非酒精性脂肪性肝炎(NASH)及其进行性亚型。然而，这个角色和 UPR信号在NASH发病机制中的作用机制尚不清楚。普遍定期审议包括 由ER蛋白IRE1α、PERK和ATF6激活的三条通路中的一条。这些蛋白质既可以服务于 作为内质网应激的传感器和信号通路的激活器。在规范的自适应IRE1α中 途径，激活的p-ir1α将XBP1拼接到激活的转录因子XBP1s中，XBP1s然后激活 保护性下游靶基因。最近的数据表明，IRE1α在细胞命运中起着重要作用 用适应性XBP1途径和凋亡调节的IRE1α依赖衰变来确定 (RIDD)和TRAF2通路。此外，IRE1α还与UPR途径相互作用。 EIF2ATF4/CHOP信号通路和其他细胞应激信号通路。虽然肝脏调节失调 IRE1α和e-IF2α通路与人类NASH相关，其起因和机制作用 IRE1α在脂肪性肝炎发病机制中的作用尚不清楚。这些项目的长期目标是 研究旨在加深我们对UPR信号在肿瘤发生发展中的作用的理解 纳什的名字。这项资助计划的目标是进一步确定肝脏IRE1α适应性和 细胞凋亡信号在非酒精性脂肪性肝炎发病机制中的作用我们之前已经演示过 当喂食高脂饮食时，肝细胞特异性缺失XBP1的小鼠更容易患上 发展纳什。我们现在提出三个具体目标，以进一步研究IRE1α信号在 脂肪性肝炎的发病机制：确定肝脏IRE1α信号增强增加 高喂养肝脏特异性XBP1(-/-)和肝脏特异性IRE1α(-/-)小鼠患脂肪性肝炎的易感性 脂肪饮食(目标1)：肝脏IRE1α通过TRAF2、eIF2α和RIDD对细胞凋亡的调控 途径(目标2)；并利用肝脏特异性细胞培养和培养的肝细胞来确定 IRE1α信号在肝细胞脂肪毒性过程中决定细胞命运(目标3)。通过更好地理解 这种IRE1α介导的适应性和凋亡信号在肝脏中可能改变平衡 决定细胞命运远离凋亡而转向适应性XBP1信号，具有潜在的治疗作用 这意味着什么。

Project Summary Non-alcoholic fatty liver disease (NAFLD) is the most common cause of abnormal liver function tests in the United States and is a major cause of cirrhosis, hepatocellular carcinoma and death. Although fatty liver disease is associated with the metabolic syndrome, the pathogenesis remains poorly understood. In the liver, the fidelity for protein folding is imperfect, and therefore excess misfolded or unfolded proteins may accumulate, a condition termed ER stress. The Unfolded Protein Response (UPR) is a protective signaling response present in all eukaryotic cells, and human and animal studies indicate that the UPR is important in NAFLD and its progressive sub-type of non-alcoholic steatohepatitis (NASH). However, the role and mechanisms of UPR signaling in the pathogenesis of NASH remains poorly understood. The UPR consists of three pathways that are activated by the ER proteins IRE1α, PERK and ATF6. These proteins serve both as sensors of ER stress and activators of their signaling pathways. In the canonical adaptive IRE1α pathway, activated p-IRE1α splices XBP1 into the active transcription factor XBP1s, which then activates protective downstream target genes. More recent data indicates that IRE1α has a major role in cell fate determination, with both the adaptive XBP1 pathway, and apoptotic Regulated Ire1α-Dependent Decay (RIDD) and TRAF2 pathways. In addition, IRE1α interacts with the UPR pathway involved with eIF2α/ATF4/CHOP signaling and other cellular stress signaling pathways. Although dysregulation of liver IRE1α and e-IF2α pathways have been associated with human NASH, the causative and mechanistic role of IRE1α in the pathogenesis of steatohepatitis remain poorly understood. The long-term goals of these studies are to enhance our understanding of the role of UPR signaling in the pathogenesis and progression of NASH. The objectives of this grant proposal are to further define the role of hepatic IRE1α adaptive and apoptotic signaling in the pathogenesis of non-alcoholic steatohepatitis. We have previously demonstrated that when fed a high fat diet, mice with hepatocyte-specific deletion of Xbp1 have increased susceptibility to develop NASH. We now propose three Specific Aims to further investigate the role of IRE1α signaling in the pathogenesis of steatohepatitis: to determine that enhanced hepatic IRE1α signaling increases the susceptibility to develop steatohepatitis using liver-specific XBP1(-/-) and liver-specific IRE1α(-/-) mice fed high fat diets (Aim 1); to delineate the regulation of apoptosis by hepatic IRE1α via the TRAF2, eIF2α and RIDD pathways (Aim 2); and to utilize liver-specific cell cultures and cultured hepatocytes to determine the role of IRE1α signaling in cell fate determination during hepatocyte lipotoxicity (Aim 3). By better understanding this IRE1α-mediated adaptive and apoptotic signaling in the liver, it may be possible to shift the balance of cell fate determination away from apoptosis and toward adaptive XBP1 signaling, with potential therapeutic implications.