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.

项目摘要 非酒精性脂肪肝疾病（NAFLD）是肝功能异常功能测试的最常见原因 美国，是肝硬化，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，发病机理仍然很少了解。在 肝脏，蛋白质折叠的保真度不完美，因此超出了杂物或展开的蛋白质 累积，一种称为ER应力的疾病。展开的蛋白质反应（UPR）是受保护的信号传导 所有真核细胞中都存在的反应，人类和动物研究表明，UPR在 NAFLD及其非酒精性脂肪性肝炎（NASH）的渐进性亚型。但是，角色和 NASH发病机理中UPR信号的机制仍然很少了解。 UPR组成 ER蛋白IRE1α，PERK和ATF6激活的三个途径。这些蛋白质两者都可以 作为ER应力的传感器和信号通路的激活剂。在规范自适应IRE1α中 途径，激活的P-ire1α将XBP1拼接到活动转录因子XBP1中，然后激活 保护性下游靶基因。最近的数据表明，IRE1α在细胞命运中具有重要作用 确定，具有自适应XBP1途径和凋亡调节的IRE1α依赖性衰减 （RIDD）和TRAF2途径。此外，IRE1α与涉及的UPR途径相互作用 EIF2α/ATF4/CHOP信号传导和其他细胞应力信号通路。虽然肝脏失调 IRE1α和E-IF2α途径与人NASH（病因和机械作用）有关 IRE1α在脂肪性肝炎的发病机理中的理解还不足。这些的长期目标 研究是为了增强我们对UPR信号在发病机理和进展中的作用的理解 纳什。该赠款提案的目标是进一步定义肝IRE1α自适应和 非酒精性脂肪性肝炎发病机理中的凋亡信号传导。我们以前已经证明了 当喂养高脂肪饮食时，XBP1的肝细胞特异性缺失的小鼠对 发展纳什。现在，我们提出了三个特定的目的，以进一步研究IRE1α信号在 脂肪性肝炎的发病机理：确定增强的肝IRE1α信号会增加 使用肝特异性XBP1（ - / - ）和肝脏特异性IRE1α（ - / - ）小鼠发育脂肪性肝炎的敏感性 脂肪饮食（AIM 1）；通过TRAF2，EIF2α和RIDD来描述肝IRE1α对凋亡的调节 途径（目标2）；并利用肝特异性细胞培养和培养的肝细胞来确定 肝细胞脂毒性期间细胞脂肪测定中的IRE1α信号传导（AIM 3）。通过更好的理解 这种IRE1α介导的自适应和凋亡信号传导，可能会改变 细胞脂肪的确定从凋亡和自适应XBP1信号转导，并具有潜在的治疗 含义。