AhR-dependent Pkm2 regulation in NAFLD progression

NAFLD 进展中 AhR 依赖性 Pkm2 调节

• 批准号: 10599120
• 负责人: Timothy R. Zacharewski
• 金额: $ 34.14万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10599120
• 关键词: Ablation; Amino Acids; Anabolism; Antioxidants; Aryl Hydrocarbon Receptor; Binding; Biological Markers; Biomass; Cell Proliferation; Cell Survival; Cells; Chemicals; Chronic Disease; Citric Acid Cycle; Compensation; Data; Defense Mechanisms; Development; Dioxins; Disease Progression; Dose; Enhancers; Environmental Pollutants; Enzymes; Epidemiology; Equilibrium; Exposure to; Fatty Liver; Fibrosis; Genetically Engineered Mouse; Glucose; Glutamine; Glutathione; Glycine; Hepatocyte; Hepatotoxicity; Histopathology; Human; Immunologic Surveillance; Impairment; Label; Ligands; Link; Liver; Malignant Neoplasms; Mediating; Metabolic; Modeling; Mus; Muscle; NADP; Normal tissue morphology; Oxidative Phosphorylation; Oxidative Stress; Pathogenicity; Pathology; Pathway interactions; Pentosephosphate Pathway; Pharmaceutical Preparations; Play; Population; Prevention; Primary carcinoma of the liver cells; Production; Prognosis; Protein Isoforms; Pyruvate Kinase; Reactive Oxygen Species; Receptor Activation; Recycling; Regulation; Reporting; Response Elements; Rodent; Role; Serine; Steatohepatitis; Testing; Tetrachlorodibenzodioxin; Therapeutic; Toxic effect; Tracer; Treatment Efficacy; Warburg Effect; Xenobiotics; aryl hydrocarbon receptor ligand; defense response; gut dysbiosis; gut microbiome; human model; knock-down; microbiome composition; mouse model; non-alcoholic fatty liver disease; novel; public health relevance; response; tumor

Project Summary The mechanism of toxicity for the environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related compounds remains poorly understood, beyond activation of the aryl hydrocarbon receptor (AhR). TCDD induces xenobiotic metabolizing enzymes with subsequent increases in reactive oxygen species (ROS). Epidemiological and rodent studies have further implicated AhR activation in the development and progression of non-alcoholic fatty liver disease (NAFLD). Our preliminary data demonstrates that AhR ligands induce a novel antioxidant mechanism involving the expression of the pyruvate kinase M2 (PKM2) isoform. PKM2 expression causes metabolic reprogramming that redirects accumulating glycolytic intermediates to the pentose phosphate pathway (PPP) and serine biosynthesis to increase NADPH levels and glutathione production in of support cellular antioxidant responses. This proposal will establish a mechanistic link between AhR activation, metabolic reprogramming, antioxidant defenses, and progression of NAFLD pathologies in mouse and human models by (1) demonstrating AhR regulation of Pkm2 expression, (2) tracking the redirection of 13C-glucose and 13C-glutamine intermediates to the PPP and glutathione biosynthesis, and (3) investigating the antioxidant role of Pkm2 in the progression of hepatic steatosis to steatohepatitis with fibrosis, modulation of tumor surveillance immune cell populations, and dysbiosis of the gut microbiome. Collectively, these studies will demonstrate that AhR-mediated PKM2 induction is a novel cellular defense mechanism, and represents a major advancement in the elucidation of the hepatotoxicity of TCDD and related compounds, with a focus on the development and progression of NAFLD.

项目摘要 环境污染物2，3，7，8-四氯二苯并对二恶英的毒性机理 (TCDD)和相关化合物除了芳基的活化外，仍然知之甚少 烃受体(AhR)。TCDD诱导的外源代谢酶与随后的 活性氧(ROS)的增加。流行病学和啮齿动物研究进一步 AhR激活在非酒精性脂肪性肝病发生发展中的作用 (NAFLD)。我们的初步数据表明，AhR配体诱导出一种新的抗氧化剂 涉及丙酮酸激酶M2(PKM2)亚型表达的机制。PKM2 表达导致代谢重编程，重定向积累的糖酵解中间产物 与磷酸戊糖途径(PPP)和丝氨酸生物合成有关，以增加NADPH水平和 谷胱甘肽的产生支持细胞的抗氧化反应。这项提议将建立一个 AhR激活、代谢重编程、抗氧化剂防御和 非酒精性脂肪肝在小鼠和人类模型中的病理研究进展：(1)论证AhR 调节PKM2的表达，(2)跟踪13C-葡萄糖和13C-谷氨酰胺的重定向 PPP和谷胱甘肽生物合成的中间体，以及(3)抗氧化作用的研究 PKM2在脂肪性肝炎肝纤维化、肿瘤调节中的作用 监测免疫细胞群和肠道微生物群的失调。总而言之，这些 研究表明，AhR介导的PKM2诱导是一种新的细胞防御机制 机制，是阐明TCDD肝毒性的重大进展 以及相关化合物，重点介绍NAFLD的发展和进展。