Hepatic stellate cell–specific knockout of transcriptional intermediary factor 1γ aggravates liver fibrosis

Abstract

Transforming growth factor beta (TGF beta) is a crucial factor in fibrosis, and transcriptional intermediary factor 1 gamma (TIF1 gamma) is a negative regulator of the TGF beta 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 TIF1 gamma was significantly decreased in LX2 cells when exposed to TGF beta 1. Such decrease of TIF1 gamma was significantly prevented by co-culture with hE-MSCs. Interaction of TIF1 gamma with SMAD2/3 and binding to the promoter of the alpha-smooth muscle gene (alpha SMA) suppressed alpha SMA expression. Phosphorylation of cAMP response element-binding protein (CREB) and binding on the TIF1 gamma promoter region induced TIF1 gamma expression. Furthermore, hepatic stellate cell-specific TIF1 gamma-knockout mice showed aggravation of liver fibrosis. In conclusion, loss of TIF1 gamma aggravates fibrosis, suggesting that a strategy to maintain TIF1 gamma during liver injury would be a promising therapeutic approach to prevent or reverse liver fibrosis.