Activation of a Novel c-Myc-miR27-Prohibitin 1 Circuitry in Cholestatic Liver Injury Inhibits Glutathione Synthesis in Mice

Abstract Aims: We showed that chronic cholestatic liver injury induced the expression of c-Myc but suppressed that of glutamate-cysteine ligase (GCL, composed of catalytic and modifier subunits GCLC and GCLM, respectively). This was associated with reduced nuclear antioxidant response element (ARE) binding by nuclear factor-erythroid 2 related factor 2 (Nrf2). Here, we examined whether c-Myc is involved in this process. Results: Similar to bile duct ligation (BDL), lithocholic acid (LCA) treatment in vivo induced c-Myc but suppressed GCL subunits expression at day 14. Nrf2 expression and Nrf2 ARE binding fell markedly. However, Nrf2 heterodimerization with MafG was enhanced by LCA, which prompted us to examine whether LCA treatment in vivo altered proteins that bind to ARE using biotinylated ARE in pull-down assay followed by proteomics. LCA treatment enhanced c-Myc but lowered prohibitin 1 (PHB1) binding to ARE. This was a result of c-Myc-mediated induction of microRNA 27a/b (miR27a/b), which target both...