Inhibition of notch signaling pathway prevents cholestatic liver fibrosis by decreasing the differentiation of hepatic progenitor cells into cholangiocytes
Inhibition of notch signaling pathway prevents cholestatic liver fibrosis by decreasing the differentiation of hepatic progenitor cells into cholangiocytes
复制标题
抑制Notch信号通路通过减少肝祖细胞向胆管细胞的分化来预防胆汁淤积性肝纤维化
DOI：
10.1038/labinvest.2015.149
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发表时间：
2016-03-01
影响因子：
5
通讯作者：
Liu, Ping
中科院分区：
文献类型：
--
作者：
Zhang, Xiao;Du, Guangli;Liu, Ping
虽然已知肝祖细胞（HPC）有助于胆汁淤积性肝纤维化（CLF），但Notch信号传导如何调节HPC向CLF中胆管细胞的分化尚不清楚。因此，使用胆管结扎诱导的CLF大鼠模型，我们用DAPT抑制Notch信号传导。在体内，CK 19、OV 6、Sox 9和EpCAM表达显著增加。胆管结扎后Notch信号传导增加，DAPT治疗降低了CK 19、OV 6、Sox 9和EpCAM的表达，并阻断了胆管细胞增殖和CLF。在体外，用丁酸钠处理WB-F344细胞系导致CK 19、Sox 9和EpCAM的mRNA和蛋白表达增加，但Notch信号被激活。这两个过程都被DAPT抑制。这项研究表明，Notch信号通路激活是需要HPC分化为胆管细胞在CLF，和Notch信号通路的抑制可能提供了一种治疗CLF的治疗方法。
Although hepatic progenitor cells (HPCs) are known to contribute to cholestatic liver fibrosis (CLF), how Notch signaling modulates the differentiation of HPCs to cholangiocytes in CLF is unknown. Thus, using a rat model of CLF that is induced by bile duct ligation, we inhibited Notch signaling with DAPT. In vivo, CK19, OV6, Sox9, and EpCAM expression was increased significantly. Notch signaling increased after bile duct ligation, and DAPT treatment reduced the expression of CK19, OV6, Sox9, and EpCAM and blocked cholangiocyte proliferation and CLF. In vitro, treatment of a WB-F344 cell line with sodium butyrate resulted in increased mRNA and protein expression of CK19, Sox9, and EpCAM, but Notch signaling was activated. Both of these processes were inhibited by DAPT. This study reveals that Notch signaling activation is required for HPC differentiation into cholangiocytes in CLF, and inhibition of the Notch signaling pathway may offer a therapeutic approach for treating CLF.