The Unfolded Protein Response in Fatty Liver

脂肪肝中未折叠的蛋白质反应

• 批准号: 10375371
• 负责人: Richard M Green
• 金额: $ 40.55万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10375371
• 关键词: ATF6 gene; Alcohols; Animals; Apoptosis; Apoptotic; Applications Grants; Binding Proteins; Cell Culture Techniques; Cell Survival; Cells; Cellular Stress; Cellular biology; Cessation of life; Cholestasis; Cirrhosis; Data; Endoplasmic Reticulum; Equilibrium; Eukaryotic Cell; FDA approved; Fatty Liver; Gene Proteins; Genes; Genetic; Goals; Hepatic; Hepatitis; Hepatocyte; High Fat Diet; Homeostasis; Human; Impairment; Inositol; Investigation; Liver; Liver Function Tests; Liver diseases; MAPK8 gene; Mediating; Medical; Metabolic syndrome; Modeling; Molecular Biology; Molecular Genetics; Mus; Obesity; Pathogenesis; Pathway interactions; Phosphorylation; Phosphotransferases; Physiology; Predisposition; Primary carcinoma of the liver cells; Protein Kinase; Proteins; RNA; RNA Splicing; Regulation; Role; Secretory Cell; Signal Pathway; Signal Transduction; Steatohepatitis; TRAF2 gene; Testing; Therapeutic; United States; Viral hepatitis; XBP1 gene; drug induced liver injury; endoplasmic reticulum stress; fatty liver disease; genetic approach; lipid metabolism; liver injury; liver transplantation; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; protein folding; response; sensor; transcription factor

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.

项目概要 非酒精性脂肪性肝病（NAFLD）是肝功能检查异常的最常见原因 在美国，它是肝硬化、肝细胞癌和死亡的主要原因。 该疾病与代谢综合征有关，但其发病机制仍知之甚少。 肝脏中，蛋白质折叠的保真度并不完美，因此过量的错误折叠或未折叠的蛋白质可能 累积，一种称为 ER 应激的情况，是一种保护性信号传导。 所有真核细胞中都存在反应，人类和动物研究表明 UPR 在 NAFLD及其进行性亚型非酒精性脂肪性肝炎(NASH)的作用和作用却是不同的。 UPR 信号在 NASH 发病机制中的机制仍知之甚少。 ER 蛋白 IRE1α、PERK 和 ATF6 激活的三种途径中的这些蛋白均发挥作用。 在典型的适应性 IRE1α 中作为 ER 应激传感器和信号通路激活剂。 途径，激活的 p-IRE1α 将 XBP1 剪接到活性转录因子 XBP1s 中，然后激活 最近的数据表明 IRE1α 在细胞命运中发挥着重要作用。 测定，同时具有适应性 XBP1 途径和凋亡调节 Ire1α 依赖性衰变 (RIDD) 和 TRAF2 途径此外，IRE1α 与参与的 UPR 途径相互作用。 eIF2α/ATF4/CHOP 信号传导和其他细胞应激信号传导途径虽然肝脏失调。 IRE1α 和 e-IF2α 通路与人类 NASH 及其致病和机制作用相关 IRE1α 在脂肪性肝炎发病机制中的作用仍知之甚少。 研究旨在增强我们对 UPR 信号在发病机制和进展中的作用的理解 NASH 资助提案的目标是进一步明确肝脏 IRE1α 适应性和功能的作用。 我们之前已经证明了非酒精性脂肪性肝炎发病机制中的细胞凋亡信号。 当喂食高脂肪饮食时，肝细胞特异性缺失 Xbp1 的小鼠对以下疾病的易感性增加 我们现在提出三个具体目标来进一步研究 IRE1α 信号在 NASH 中的作用。 脂肪性肝炎的发病机制：确定增强的肝脏 IRE1α 信号传导会增加 使用高饲喂肝脏特异性 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）；描述肝脏 IRE1α 通过 TRAF2、eIF2α 和 RIDD 对细胞凋亡的调节 途径（目标 2）；并利用肝脏特异性细胞培养物和培养的肝细胞来确定 肝细胞脂毒性过程中细胞命运决定中的 IRE1α 信号传导（目标 3）。 这种 IRE1α 介导的肝脏适应性和凋亡信号传导，可能会改变肝脏中的平衡 细胞命运决定从细胞凋亡转向适应性 XBP1 信号传导，具有潜在的治疗作用 影响。