Hepatocyte-specific deletion of Brg1 prevents CCl4-induced liver fibrosis in mice

Background & aims:

Brg1 is the core subunit of the SWI/SNF chromatin remodeling complex and is involved in the regulation of liver regeneration. Hepatic fibrosis is a progressive pathological process that results in the accumulation of excessive extracellular matrix proteins, ultimately leading to the development of cirrhosis. So far, the role of Brg1 in liver fibrosis remains unclear. In this study, we investigated the effect of Brg1 on the progression of liver fibrosis.

Methods:

We used a hepatocyte-specific Brg1 knockout mouse model (AlbCre Brg1fl/fl). Carbon tetrachloride (CCl4) was injected to induce liver fibrosis for 4, 6, 8, and 12 weeks. Brg1 expression was determined by Western blot. Liver fibrosis was evaluated by analysis of liver-to-body weight ratio, serum ALT ELISA, Sirius red staining, and alpha-smooth muscle actin (a-SMA) staining.

Results:

Brg1 expression was significantly increased in fibrotic liver tissue of wild-type mice compared to untreated wild-type mice. Brg1 knockout mice showed reduced liver fibrosis after chronic liver injury caused by CCl4 injection. After 6 weeks of CCl4 treatment, the liver-to-body weight ratio of Brg1 hepatocyte-specific knockout mice was significantly reduced compared to wildtype mice. Furthermore, as shown by Sirius red and α-SMA staining, significantly less fibrosis was observed in Brg1 knockout mice. In addition, Brg1 knockout mice had significantly lower serum ALT levels compared to wild-type mice.

Conclusions:

We demonstrated that hepatocyte-specific Brg1 deletion prevents liver fibrosis in CCl4-treated mice. We conclude that Brg1 promotes the progression of liver fibrosis and can therefore be used as a potential therapeutic target for the treatment of patients with liver fibrosis due to chronic injury.