Yan Fang-Zhi, Qian Hui, Liu Fang, Ding Chen-Hong, Liu Shu-Qing, Xiao Meng-Chao, Chen Shi-Jie, Zhang Xin, Luo Cheng, Xie Wei-Fen
Department of Gastroenterology, Changzheng Hospital, Naval Medical University, Shanghai, China.
Department of Gastroenterology, Shanghai East Hospital, Tongji University of School of Medicine, Shanghai, China.
FASEB J. 2022 Sep;36(9):e22489. doi: 10.1096/fj.202200238R.
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.
据报道，蛋白质精氨酸甲基转移酶1（PRMT1）与多种疾病有关。在人类患者的肝硬化肝脏中，PRMT1的表达增加。然而，PRMT1在肝纤维化形成中的作用在很大程度上仍未得到探索。在本研究中，我们研究了PRMT1对肝纤维化形成的影响及其潜在机制。我们发现，在用硫代乙酰胺（TAA）或3,5 - 二乙氧羰基 - 1,4 - 二氢可力丁（DDC）饮食处理的小鼠纤维化肝脏中，PRMT1的表达显著更高。免疫荧光染色显示，在纤维化肝脏的肝细胞和肝星状细胞（HSC）中，PRMT1的表达均增加。应用PRMT1的选择性抑制剂PT1001B可显著抑制PRMT1活性，并减轻小鼠肝纤维化。肝细胞特异性Prmt1基因敲除不影响小鼠肝纤维化。PRMT1过表达促进LX - 2细胞中纤维化基因的表达，而PRMT1的敲低或用PT1001B处理则表现出相反的效果，这表明PRMT1在HSC激活中起重要作用。此外，在TAA诱导的纤维化模型中，HSC特异性Prmt1基因敲除减弱了HSC激活和肝纤维化。RNA测序分析显示，HSC中Prmt1基因敲除显著抑制促炎NF - κB和促纤维化TGF - β信号，并下调小鼠肝脏中促纤维化介质的表达。此外，用PT1001B处理在纤维化模型中持续抑制肝脏炎症反应。总之，PRMT1在HSC激活中起关键作用。抑制PRMT1可通过减轻小鼠HSC激活来减轻肝纤维化。因此，靶向PRMT1可能是肝纤维化的一种可行治疗策略。
