Hepatocellular Brg1 Promotes CCl4-Induced Liver Inflammation, ECM Accumulation and Fibrosis

Abstract

Introduction: Brahma-related gene 1 (Brg1) is a catalytic subunit of the SWI/SNF complex and has recently been identified as important for liver regeneration. Liver fibrosis is a progressive pathological process that results in the depletion of the hepatocellular regenerative capacity and ultimately leads to the development of liver cirrhosis and even hepatocellular carcinoma. So far the role of Brg1 in liver fibrosis is unclear. Method: In this study, we examined the effect of Brg1 on the development of liver fibrosis. Hepatocyte-specific Brg1 knockout mice (AlbCre Brg1fl/fl) were injected with CCl4 to induce liver fibrosis. Brg1 expression was determined by Western blot and liver fibrosis was assessed by liver-to-body weight ratio analysis, serum ALT ELISA, Sirius red staining, and alpha-smooth muscle actin staining. Results: Brg1 expression was significantly increased in the fibrotic liver tissue of wild-type mice compared to untreated wild-type mice. The livers of the Brg1 knockout animals showed a significantly reduced liver inflammation, extracellular matrix accumulation and liver fibrosis compared to wild-type mice. Furthermore, we were able to show that HSC activation and inflammatory response during CCl4-induced liver fibrosis are associated with Brg1, which mediates the TNF-α/NF-kB pathway. Conclusions: These results highlight a new aspect of Brg1 in the pathogenesis of liver fibrosis. We have shown that hepatocyte-specific Brg1 deletion prevents liver fibrosis in CCl4-treated mice. In conclusion, Brg1 promotes the progression of liver fibrosis in mice and therefore can be used as a potential therapeutic target for the treatment of patients with liver fibrosis due to chronic injury.