Disruption of canonical AHR-mediated induction of hepatocyte PKM2 expression compromises antioxidant defenses and increases TCDD-induced hepatotoxicity.

ABSTRACT: 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^ΔDRE mouse was constructed lacking the dioxin response element mediating aryl hydrocarbon receptor (AHR) induction. TCDD failed to induce hepatic PKM2 in Pkm^ΔDRE mice and in primary hepatocytes isolated from an AHR knockout model (AHR^V375Afl/flAlb-Cre^ERT2), demonstrating induction is AHR dependent. Both wild-type (WT) and Pkm^ΔDRE mice exhibit

SUBMITTER: Orlowska K 

PROVIDER: S-EPMC11543540 | biostudies-literature | 2024 Nov

REPOSITORIES: biostudies-literature