AhR-dependent Pkm2 regulation in NAFLD progression

NAFLD 进展中 AhR 依赖性 Pkm2 调节

• 批准号: 10597776
• 负责人: Timothy R. Zacharewski
• 金额: $ 4.03万
• 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 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10597776
• 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; Data; Defense Mechanisms; Development; Dioxins; Disease Progression; Dose; Enhancers; Environmental Pollution; 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.

项目概要 环境污染物2,3,7,8-四氯二苯并-对二恶英的毒性机制 （TCDD）和相关化合物除了芳基的活化之外仍然知之甚少 碳氢化合物受体（AhR）。 TCDD 诱导异生物质代谢酶，随后 活性氧（ROS）增加。流行病学和啮齿动物研究进一步 AhR 激活与非酒精性脂肪肝疾病的发生和进展有关 （非酒精性脂肪肝）。我们的初步数据表明 AhR 配体诱导一种新型抗氧化剂 机制涉及丙酮酸激酶 M2 (PKM2) 亚型的表达。 PKM2 表达引起代谢重编程，从而重定向积累的糖酵解中间体 磷酸戊糖途径 (PPP) 和丝氨酸生物合成，以增加 NADPH 水平和 谷胱甘肽的产生支持细胞的抗氧化反应。该提案将设立一个 AhR 激活、代谢重编程、抗氧化防御和 通过 (1) 证明 AhR 来研究小鼠和人类模型中 NAFLD 病理的进展 Pkm2 表达的调节，(2) 追踪 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) 研究抗氧化作用 Pkm2 在肝脂肪变性进展为伴有纤维化的脂肪性肝炎、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。总的来说，这些 研究将证明 AhR 介导的 PKM2 诱导是一种新型细胞防御 机制，代表了阐明 TCDD 肝毒性的重大进展 以及相关化合物，重点关注 NAFLD 的发生和进展。