Loss of Dioxin Response Element-Mediated Induction of PKM2 Reprograms Hepatic Metabolism in Response to TCDD

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) reprograms central carbon metabolism by switching pyruvate kinase expression from isoform M1 (Pkm1) to M2 (Pkm2), mediated by aryl hydrocarbon receptor (AhR) binding to a dioxin response element (DRE) located between exons 3 and 4 within the Pkm locus. To further investigate the consequences of Pkm isoform switching in TCDD elicited hepatotoxicity, we examined gene expression in primary hepatocytes isolated from mice with the Pkm locus DRE excised (Pkm^ΔDRE). Wild-type and Pkm^ΔDRE hepatocytes were treated with 10 nM TCDD for 2, 4, 8, 12, 24, 48, 72, 96 and 120 h. Central carbon metabolite changes were also assessed in WT and Pkm^ΔDRE mice treated with 30 µg/kg TCDD every 4 day for 28 days. While AHR target genes were comparably induced, some genes exhibited divergent expression patterns in Pkm^ΔDRE mice compared to wild-types following treatment with TCDD. Notably, antioxidant gene expression was delayed in Pkm^ΔDRE hepatocytes. Metabolomic analysis also revealed differences in glycolytic, TCA cycle and pentose phosphate pathway metabolite levels in TCDD-treated WT and Pkm^ΔDRE liver extracts. In addition, amino acid metabolism and serine/glycine synthesis were also elevated, especially in Pkm^ΔDRE. These findings indicate PKM2 induction affects the transcriptional and metabolic coordination of hepatic responses to TCDD.