Hepatic stellate cell-specific knockout of transcriptional intermediary factor 1gamma aggravates liver fibrosis.

Transforming growth factor beta (TGFbeta) is a crucial factor in fibrosis, and transcriptional intermediary factor 1gamma (TIF1gamma) is a negative regulator of the TGFbeta pathway; however, its role in liver fibrosis is unknown. In this study, mesenchymal stem cells derived from human embryonic stem cells (hE-MSCs) that secrete hepatocyte growth factor (HGF) were used to observe the repair of thioacetamide (TAA)-induced liver fibrosis. Our results showed that TIF1gamma was significantly decreased in LX2 cells when exposed to TGFbeta1. Such decrease of TIF1gamma was significantly prevented by co-culture with hE-MSCs. Interaction of TIF1gamma with SMAD2/3 and binding to the promoter of the alpha-smooth muscle gene (alphaSMA) suppressed alphaSMA expression. Phosphorylation of cAMP response element-binding protein (CREB) and binding on the TIF1gamma promoter region induced TIF1gamma expression. Furthermore, hepatic stellate cell-specific TIF1gamma-knockout mice showed aggravation of liver fibrosis. In conclusion, loss of TIF1gamma aggravates fibrosis, suggesting that a strategy to maintain TIF1gamma during liver injury would be a promising therapeutic approach to prevent or reverse liver fibrosis.