Targeting the chromatin remodeling protein BRG1 in liver fibrosis: Mechanism and translational potential

Aims: Liver fibrosis is characterized by excessive deposition of extracellular matrix (ECM) proteins in the interstitia. Hepatic stellate cells (HSCs) are considered the major source for ECM-producing myofibroblasts contributing to liver fibrosis. The molecular mechanism whereby HSC-myofibroblast transition is regulated remains incompletely understood. We investigated the involvement of BRG1, a chromatin remodeling protein, in this process.Methods: Rosa26-Smarca4 mice were crossed to Lrat-Cre mice to generate HSC-specific BRG1 transgenic mice. Liver fibrosis was induced by bile duct ligation (BDL) or injection with carbon tetrachloride (CCl4).Results: We report here that over-expression of BRG1 promoted HSC-myofibroblast transition in vitro. More importantly, the BRG1 transgenic mice displayed amplification of liver fibrogenesis, induced by BDL or CCl4 injection, compared to the wild type littermates. On the contrary, BRG1 inhibition by a small-molecule compound (PFI-3) attenuated HSC-myofibroblast transition in vitro and ameliorated liver fibrosis in a dose-dependent manner in mice. RNA-seq analysis showed that PFI-3 treatment preferentially influenced the expression of ECM genes in activated HSCs. Conclusion: Our data provide strong evidence that BRG1 plays an important role in HSC-myofibroblast transition and suggest that targeting BRG1 could be considered as a reasonable strategy for the intervention of liver fibrosis.