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

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.

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).

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.

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.