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 proinflammatory 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.

Protein arginine methyltransferases in renal development, injury, repair, and fibrosis

“…In addition, the profibrotic role of PRMT1 was also observed in lung and liver tissue (Zakrzewicz et al, 2015). Observed that expression of PRMT1 was increased in IPF (idiopathic pulmonary fibrosis) lung fibroblasts and IPF lungs and in lungs of bleomycin-treated mice, and PRMT1 knockdown or inhibition of PRMT activity reduced IPF fibroblast motility (Yan et al, 2022). Found that the expression of PRMT1 was elevated in cirrhotic livers from human patients and in fibrotic livers of the mouse models, and the application of a selective inhibitor of PRMT1, PT1001B, or hepatic stellate cells (HSC)-specific PRMT1 knockout attenuated HSC activation and liver fibrosis in fibrotic models.…”

Identification and validation of anti-protein arginine methyltransferase 5 (PRMT5) antibody as a novel biomarker for systemic sclerosis (SSc)

“…PRMT5 has been reported to regulate T cells through various pathways, including promoting retinoid-related orphan receptor (ROR)-γt activity and adjusting the Klf2-S1pr1 pathway 41 42. Arginine methylation mediated by PRMTs has emerged as a critical mechanism implicated in fibrosis 43–47. Notably, fibroblast-specific deletion of PRMT5 significantly reduced pressure overload-induced cardiac fibrosis.…”