Liver‐specific deletion of microRNA ‐34a alleviates ductular reaction and liver fibrosis during experimental cholestasis
Liver‐specific deletion of microRNA ‐34a alleviates ductular reaction and liver fibrosis during experimental cholestasis
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肝脏特异性删除 microRNA 34a 可减轻实验性胆汁淤积期间的导管反应和肝纤维化
DOI：
10.1096/fj.202201453r
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发表时间：
2022
期刊：
影响因子：
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通讯作者：
Fanyin Meng
中科院分区：
文献类型：
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作者：
Ying Wan;Tianhao Zhou;Elise Slevin;Sachiko Koyama;Xuedong Li;Kelly Harrison;Tian Li;Bingru Zhou;Sugeily Ramos Lorenzo;Yudian Zhang;Wenjuan Xu;James E. Klaunig;Chaodong Wu;Ashok K. Shetty;Chiung‐Kuei Huang;Fanyin Meng
原发性硬化性胆管炎（PSC）是一种慢性肝病，其特征是炎症反应和纤维化瘢痕形成，导致胆汁淤积。胆管反应和肝纤维化是在人PSC和胆汁淤积患者中观察到的典型肝脏变化。目前的研究旨在阐明肝脏特异性microRNA-34 a在胆汁淤积相关的导管反应和肝纤维化中的作用。我们证明，miR-34 a表达在人PSC肝脏中显著增加，沿着增强的小管反应、细胞衰老和肝纤维化。通过将floxed miR-34 a小鼠与白蛋白启动子驱动的Cre小鼠杂交建立肝脏特异性miR-34 a敲除小鼠。胆管结扎（BDL）引起的肝损伤的特点是坏死，纤维化和免疫细胞浸润。相比之下，BDL小鼠中肝脏特异性miR-34 a敲除导致胆管病理学减少，与胆管细胞衰老和纤维化反应减少相关。miR-34 a介导的小管反应可能通过Sirt-1介导的衰老和纤维化发挥作用。肝细胞来源的条件培养基促进了LPS诱导的胆管细胞纤维化反应和衰老，而miR-34 a抑制剂抑制了这些作用，进一步支持了旁分泌调节的参与。总之，我们证明了肝脏特异性miR-34 a在胆汁淤积性肝病BDL小鼠模型中的小管反应和纤维化反应中起重要作用。
Primary sclerosing cholangitis (PSC) is a chronic liver disease characterized by inflammatory responses and fibrotic scar formation leading to cholestasis. Ductular reaction and liver fibrosis are typical liver changes seen in human PSC and cholestasis patients. The current study aimed to clarify the role of liver‐specific microRNA‐34a in the cholestasis‐associated ductular reaction and liver fibrosis. We demonstrated that miR‐34a expression was significantly increased in human PSC livers along with the enhanced ductular reaction, cellular senescence, and liver fibrosis. A liver‐specific miR‐34a knockout mouse was established by crossing floxed miR‐34a mice with albumin‐promoter‐driven Cre mice. Bile duct ligation (BDL) induced liver injury characterized by necrosis, fibrosis, and immune cell infiltration. In contrast, liver‐specific miR‐34a knockout in BDL mice resulted in decreased biliary ductular pathology associated with the reduced cholangiocyte senescence and fibrotic responses. The miR‐34a‐mediated ductular reactions may be functioning through Sirt‐1‐mediated senescence and fibrosis. The hepatocyte‐derived conditioned medium promoted LPS‐induced fibrotic responses and senescence in cholangiocytes, and miR‐34a inhibitor suppressed these effects, further supporting the involvement of paracrine regulation. In conclusion, we demonstrated that liver‐specific miR‐34a plays an important role in ductular reaction and fibrotic responses in a BDL mouse model of cholestatic liver disease.