Inhibition of protein arginine methyltransferase 1 alleviates liver fibrosis by attenuating the activation of hepatic stellate cells in mice

Abstract Protein arginine methyltransferase 1 (PRMT1) has been reported to be involved in various diseases. The expression of PRMT1 was increased in cirrhotic livers from human patients. However, the role of PRMT1 in hepatic fibrogenesis remains largely unexplored. In this study, we investigated the effect of PRMT1 on hepatic fibrogenesis and its underlying mechanism. We found that PRMT1 expression was significantly higher in fibrotic livers of the mice treated with thioacetamide (TAA) or 3,5‐diethoxycarbonyl‐1,4‐dihydrocollidine (DDC) diet. Immunofluorescence staining revealed that PRMT1 expression was augmented in both hepatocytes and hepatic stellate cells (HSCs) in the fibrotic livers. Applying a selective inhibitor of PRMT1, PT1001B, significantly suppressed PRMT1 activity and mitigated liver fibrosis in mice. Hepatocyte‐specific Prmt1 knockout did not affect liver fibrosis in mice. PRMT1 overexpression promoted the expression of fibrotic genes in the LX‐2 cells, whereas knockdown of PRMT1 or treatment with PT1001B exhibited reversal effects, suggesting that PRMT1 plays an important role in HSC activation. Additionally, HSC‐specific Prmt1 knockout attenuated HSC activation and liver fibrosis in TAA‐induced fibrotic model. RNA‐seq analysis revealed that Prmt1 knockout in HSCs significantly suppressed pro‐inflammatory NF‐κB and pro‐fibrotic TGF‐β signals, and also downregulated the expression of pro‐fibrotic mediators in mouse livers. Moreover, treatment with PT1001B consistently inhibited hepatic inflammatory response in fibrotic model. In conclusion, PRMT1 plays a vital role in HSC activation. Inhibition of PRMT1 mitigates hepatic fibrosis by attenuating HSC activation in mice. Therefore, targeting PRMT1 could be a feasible therapeutic strategy for liver fibrosis.