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.

LanguageEnglish (US)
Article numberkfv245
Pages358-371
Number of pages14
JournalToxicological Sciences
Volume149
Issue number2
DOIs
StatePublished - Feb 1 2016

Profile

Pyruvate Kinase
Aryl Hydrocarbon Receptors
Protein Isoforms
Impurities
NADP
Liver
Fluxes
Glutaminase
Pentoses
Gene Expression
Pentose Phosphate Pathway
Dioxins
Metabolomics
Data integration
Biosynthesis
Response Elements
Glycolysis
Metabolites
Inbred C57BL Mouse
Folic Acid

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

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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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