AhR-dependent Pkm2 regulation in NAFLD progression

NAFLD 进展中 AhR 依赖性 Pkm2 调节

基本信息

批准号：
9904679
负责人：
Timothy R. Zacharewski
金额：
$ 34.22万
依托单位：
MICHIGAN STATE UNIVERSITY
依托单位国家：
美国
项目类别：
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/9904679
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 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 combat defense response dysbiosis gut microbiome human model knock-down microbiome composition mouse model non-alcoholic fatty liver disease novel outcome forecast public health relevance response tumor

项目摘要

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2,3,7,8-四氯苯二甲酸-P-二恶英的毒性机制（TCDD）和相关化合物的理解仍然不足，超出了芳基的激活碳氢化合物受体（AHR）。 TCDD诱导异生物代谢酶，随后活性氧（ROS）的增加。流行病学和啮齿动物研究进一步与非酒精性脂肪肝病的发育和进展相关的AHR激活（NAFLD）。我们的初步数据表明，AHR配体会诱导一种新颖的抗氧化剂涉及丙酮酸激酶M2（PKM2）同工型表达的机制。 PKM2 表达导致代谢重编程，以重定向累积的糖酵解中间体到戊糖磷酸途径（PPP）和丝氨酸生物合成，以增加NADPH水平和支持细胞抗氧化剂反应的谷胱甘肽产生。该建议将建立一个 AHR激活，代谢重编程，抗氧化剂防御和通过（1）证明AHR的小鼠和人类模型中NAFLD病理的进展 PKM2表达的调节，（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，（3）研究抗氧化作用 PKM2在肝脂肪变性到脂肪性肝炎的进展中的纤维化，调节肿瘤监测免疫细胞群和肠道微生物组的营养不良。总的来说，这些研究将表明AHR介导的PKM2诱导是一种新型的细胞防御机制，代表了阐明TCDD肝毒性的重大进步和相关的化合物，重点是NAFLD的发展和发展。