| First Author | Orlowska K | Year | 2024 |
| Journal | Redox Biol | Volume | 77 |
| Pages | 103405 | PubMed ID | 39490313 |
| Mgi Jnum | J:358467 | Mgi Id | MGI:7780928 |
| Doi | 10.1016/j.redox.2024.103405 | Citation | Orlowska K, et al. (2024) Disruption of canonical AHR-mediated induction of hepatocyte PKM2 expression compromises antioxidant defenses and increases TCDD-induced hepatotoxicity. Redox Biol 77:103405 |
| abstractText | Metabolic reprogramming by the pyruvate kinase M2 isoform is associated with cell proliferation and reactive oxygen species (ROS) defenses. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), an environmental contaminant that induces ROS and hepatotoxicity, dose-dependently induces pyruvate kinase muscle isoform M2 (PKM2) in the liver. To further investigate its role in combating TCDD hepatotoxicity, a Pkm(DeltaDRE) mouse was constructed lacking the dioxin response element mediating aryl hydrocarbon receptor (AHR) induction. TCDD failed to induce hepatic PKM2 in Pkm(DeltaDRE) mice and in primary hepatocytes isolated from an AHR knockout model (AHR(V375Afl/fl)Alb-Cre(ERT2)), demonstrating induction is AHR dependent. Both wild-type (WT) and Pkm(DeltaDRE) mice exhibited dose-dependent increases in liver weight after treatment with TCDD every 4 days for 28 days. Glutathione (GSH) levels increased in WT mice while oxidized glutathione (GSSG) levels increased in both models with a 24-fold decrease in the GSH/GSSG ratio in Pkm(DeltaDRE) mice suggesting lower antioxidant and recycling capacity. Moreover, TCDD-induced fibrosis was more severe in Pkm(DeltaDRE) mice while Pkm(DeltaDRE) hepatocytes exhibited greater cytotoxicity following co-treatment with TCDD and hydrogen peroxide. TCDD also induced PKM2 in human HepaRG cells with AHR enrichment at a conserved DRE core within the locus. These results suggest AHR-mediated PKM2 induction is a novel antioxidant response to TCDD. |
