Orphan nuclear receptor ERRγ regulates hepatic TGF-β2 expression and fibrogenic response in CCl₄-induced acute liver...

Acute liver injury results from the complex interactions of various pathological processes. The TGF-β superfamily plays a crucial role in orchestrating fibrogenic response. In contrast to TGF-β1, a role of TGF-β2 in hepatic fibrogenic response has not been fully investigated. In this study, we showed that TGF-β2 gene expression and secretion are induced in the liver of CCl₄ (1 ml/kg)-treated WT mice. Studies with hepatocyte specific ERRγ knockout mice or treatment with an ERRγ-specific inverse agonist, GSK5182 (40 mg/kg), indicated that CCl₄-induced hepatic TGF-β2 production is ERRγ dependent. Moreover, IL6 was found as upstream signal to induce hepatic ERRγ and TGF-β2 gene expression in CCl₄-mediated acute toxicity model. Over-expression of ERRγ was sufficient to induce hepatic TGF-β2 expression, whereas ERRγ depletion markedly reduces IL6-induced TGF-β2 gene expression and secretion in vitro and in vivo. Promoter assays showed that ERRγ directly binds to an ERR response element in the TGF-β2 promoter to induce TGF-β2 transcription. Finally, GSK5182 diminished CCl₄-induced fibrogenic response through inhibition of ERRγ-mediated TGF-β2 production. Taken together, these results firstly demonstrate that ERRγ can regulate the TGF-β2-mediated fibrogenic response in a mouse model of CC1₄-induced acute liver injury.