Open AccessHepatic stellate cell–specific knockout of transcriptional intermediary factor 1γ aggravates liver fibrosis
Author(s) -
Eun Ju Lee,
Injoo Hwang,
Ji Yeon Lee,
Jong Nam Park,
Keun Cheon Kim,
Irene Kim,
Dodam Moon,
Hyomin Park,
Seo Yeon Lee,
Hong Sug Kim,
Dae Won Jun,
Shin Young Park,
Hyo Soo Kim
Publication year - 2020
Publication title -
the journal of experimental medicine/the journal of experimental medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 8.483
H-Index - 448
eISSN - 1540-9538
pISSN - 0022-1007
DOI - 10.1084/jem.20190402
Subject(s) - hepatic stellate cell , transforming growth factor , thioacetamide , biology , hepatocyte growth factor , fibrosis , hepatic fibrosis , cancer research , conditional gene knockout , knockout mouse , transforming growth factor beta , microbiology and biotechnology , endocrinology , phenotype , medicine , receptor , gene , genetics
Transforming growth factor β (TGFβ) is a crucial factor in fibrosis, and transcriptional intermediary factor 1γ (TIF1γ) is a negative regulator of the TGFβ 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 TIF1γ was significantly decreased in LX2 cells when exposed to TGFβ1. Such decrease of TIF1γ was significantly prevented by co-culture with hE-MSCs. Interaction of TIF1γ with SMAD2/3 and binding to the promoter of the α-smooth muscle gene (αSMA) suppressed αSMA expression. Phosphorylation of cAMP response element–binding protein (CREB) and binding on the TIF1γ promoter region induced TIF1γ expression. Furthermore, hepatic stellate cell–specific TIF1γ-knockout mice showed aggravation of liver fibrosis. In conclusion, loss of TIF1γ aggravates fibrosis, suggesting that a strategy to maintain TIF1γ during liver injury would be a promising therapeutic approach to prevent or reverse liver fibrosis.