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

J Exp Med. 2020 Jun 1;217(6):e20190402. doi: 10.1084/jem.20190402.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / metabolism
  • Animals
  • Cells, Cultured
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Hepatic Stellate Cells / metabolism*
  • Hepatic Stellate Cells / pathology*
  • Hepatocyte Growth Factor / metabolism
  • Humans
  • Liver Cirrhosis / metabolism*
  • Liver Cirrhosis / pathology*
  • Male
  • Mesenchymal Stem Cell Transplantation
  • Mesenchymal Stem Cells / metabolism
  • Mice, Knockout
  • Mice, Nude
  • Mice, Transgenic
  • Phosphorylation
  • Promoter Regions, Genetic / genetics
  • Protein Binding
  • Reproducibility of Results
  • Smad Proteins / metabolism
  • Thioacetamide
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Up-Regulation

Substances

  • ACTA2 protein, human
  • Actins
  • Cyclic AMP Response Element-Binding Protein
  • Smad Proteins
  • TRIM33 protein, human
  • Transcription Factors
  • Trim33 protein, mouse
  • Thioacetamide
  • Hepatocyte Growth Factor