Pyruvate kinase isoform switching and hepatic metabolic reprogramming by the environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin

Rance Nault, Kelly A. Fader, Mathew P. Kirby, Shaimaa Ahmed, Jason Matthews, A. Daniel Jones, Sophia Y. Lunt, Timothy R. Zacharewski

    Research output: Contribution to journalArticle

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    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.

    Original languageEnglish (US)
    Article numberkfv245
    Pages (from-to)358-371
    Number of pages14
    JournalToxicological Sciences
    Volume149
    Issue number2
    DOIs
    StatePublished - Feb 1 2016

    Profile

    Tetrachlorodibenzodioxin
    Pyruvate Kinase
    Dioxins
    Protein Isoforms
    Liver
    Aryl Hydrocarbon Receptors
    NADP
    Gene Expression
    Proteins
    Berkelium
    Fluxes
    Glutaminase
    Pentose Phosphate Pathway
    Metabolomics
    Response Elements
    Glycolysis
    Inbred C57BL Mouse
    Folic Acid
    Oxidants
    Cytochrome P-450 Enzyme System

    Keywords

    • glutaminolysis
    • hepatotoxicity
    • oxidative stress
    • PKM2
    • TCDD

    ASJC Scopus subject areas

    • Toxicology

    Cite this

    Pyruvate kinase isoform switching and hepatic metabolic reprogramming by the environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin. / Nault, Rance; Fader, Kelly A.; Kirby, Mathew P.; Ahmed, Shaimaa; Matthews, Jason; Jones, A. Daniel; Lunt, Sophia Y.; Zacharewski, Timothy R.

    In: Toxicological Sciences, Vol. 149, No. 2, kfv245, 01.02.2016, p. 358-371.

    Research output: Contribution to journalArticle

    Nault, Rance; Fader, Kelly A.; Kirby, Mathew P.; Ahmed, Shaimaa; Matthews, Jason; Jones, A. Daniel; Lunt, Sophia Y.; Zacharewski, Timothy R. / Pyruvate kinase isoform switching and hepatic metabolic reprogramming by the environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin.

    In: Toxicological Sciences, Vol. 149, No. 2, kfv245, 01.02.2016, p. 358-371.

    Research output: Contribution to journalArticle

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    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.",
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