title: Pyruvate Kinase Isoform Switching and Hepatic Metabolic Reprogramming by the Environmental Contaminant 2,3,7,8-Tetrachlorodibenzo-p-Dioxin.
abstract: The environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) elicits dose-dependent hepatotoxicity that includes fat accumulation, inflammation, and fibrosis that may progress to hepatocellular carcinoma. To further investigate these effects, RNA-Seq data were integrated with computationally identified putative dioxin response elements, and complementary targeted metabolomic and aryl hydrocarbon receptor (AhR) ChIP-Seq data from female C57BL/6 mice gavaged with TCDD every 4 days for 28 days. Data integration using CytoKEGG with manual curation identified dose-dependent alterations in central carbon and amino acid metabolism. More specifically, TCDD increased pyruvate kinase isoform M2 (PKM2) gene and protein expression. PKM2 has lower catalytic activity resulting in decreased glycolytic flux and the accumulation of upstream intermediates that were redirected to the pentose phosphate pathway and serine/folate biosynthesis, 2 important NADPH producing pathways stemming from glycolysis. In addition, the GAC:KGA glutaminase (GLS1) protein isoform ratio was increased, consistent with increases in glutaminolysis which serves an anaplerotic role for the TCA cycle and compensates for the reduced glycolytic flux. Collectively, gene expression, protein, and metabolite changes were indicative of increases in NADPH production in support of cytochrome P450 activity and ROS defenses. This AhR-mediated metabolic reprogramming is similar to the Warburg effect and represents a novel advantageous defense mechanism to increase anti-oxidant capacity in normal differentiated hepatocytes.
authors.affiliation: *Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, Michigan 48824, Institute for Integrative Toxicology.
authors.forename: Rance
authors.initials: R
authors.lastname: Nault
authors.affiliation: *Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, Michigan 48824, Institute for Integrative Toxicology.
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Fader
authors.affiliation: *Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, Michigan 48824.
authors.forename: Mathew P
authors.initials: MP
authors.lastname: Kirby
authors.affiliation: Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Shaimaa
authors.initials: S
authors.lastname: Ahmed
authors.affiliation: Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON M5S 1A8, Canada, Department of Nutrition, University of Oslo, Oslo, 0316, Norway, and.
authors.forename: Jason
authors.initials: J
authors.lastname: Matthews
authors.affiliation: *Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, Michigan 48824, Department of Chemistry, Michigan State University, East Lansing, Michigan 48824.
authors.forename: A Daniel
authors.initials: AD
authors.lastname: Jones
authors.affiliation: *Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, Michigan 48824.
authors.forename: Sophia Y
authors.initials: SY
authors.lastname: Lunt
authors.affiliation: *Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, Michigan 48824, Institute for Integrative Toxicology, naultran@msu.edu tzachare@msu.edu.
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Zacharewski
mesh_terms: D000818:Animals; D004785:Environmental Pollutants / Q000633:toxicity*; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D005947:Glucose / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism*; D050356:Lipid Metabolism / Q000187:drug effects; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009249:NADP / Q000378:metabolism; D018384:Oxidative Stress; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D011770:Pyruvate Kinase / Q000378:metabolism*; D018336:Receptors, Aryl Hydrocarbon / Q000502:physiology
chemical_list: D004785:Environmental Pollutants; D005227:Fatty Acids; D007527:Isoenzymes; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; D009249:NADP; D011770:Pyruvate Kinase; D005947:Glucose
keywords: PKM2; TCDD; glutaminolysis; hepatotoxicity; oxidative stress