School of Life Science, Shaoxing University, Shaoxing, Zhejiang, China.
College of Life and Environmental Science, Hangzhou Normal University, Hangzhou, China.
Environ Toxicol. 2021 Feb;36(2):194-203. doi: 10.1002/tox.23025. Epub 2020 Sep 30.
Carbon tetrachloride (CCl ) exposure can induce hepatic ductular reactions. To date, however, the related mechanism remains largely unknown. Sonic hedgehog (Shh) and Yes-associated protein (Yap) signaling are correlated with liver injury and regeneration. Herein, we investigated the role of Shh and Yap signaling in the fate of ductular reaction cells in CCl -treated livers and the possible mechanisms. Wild-type and Shh-EGFP-Cre male mice were exposed to CCl (2 mL/kg), and then treated with or without the Shh signaling inhibitor Gant61. The level of liver injury, proliferation of ductular reaction cells, and expression levels of mRNA and protein related to the Shh and Yap signaling components were assessed. Results showed that CCl treatment induced liver injury and promoted activation and proliferation of ductular reaction cells. In addition, CCl induced the expression of Shh ligands in hepatocytes, accompanied by activation of Shh and Yap1 signaling in the liver. Furthermore, administration of Gant61 ameliorated liver regeneration, inhibited hepatic ductular reactions, and decreased Shh and Yap1 signaling activity. Thus, Shh-Yap1 signaling appears to play an integral role in the proliferation of ductular reaction cells in CCl -induced liver injury. This study should improve our understanding of the mechanism of CCl -induced liver injury and ductular reactions and provide support for future investigations on liver disease therapy.
四氯化碳（CCl ）暴露可诱导胆管反应。然而，迄今为止，其相关机制在很大程度上尚不清楚。Sonic Hedgehog（Shh）和Yes 相关蛋白（Yap）信号与肝损伤和再生有关。在此，我们研究了 Shh 和 Yap 信号在 CCl 处理肝脏中胆管反应细胞命运中的作用及其可能的机制。雄性野生型和 Shh-EGFP-Cre 小鼠接受 CCl（2ml/kg）处理，然后用或不用 Shh 信号抑制剂 Gant61 处理。评估了肝损伤程度、胆管反应细胞的增殖以及与 Shh 和 Yap 信号成分相关的 mRNA 和蛋白的表达水平。结果表明，CCl 处理可诱导肝损伤，并促进胆管反应细胞的激活和增殖。此外，CCl 诱导了肝细胞中 Shh 配体的表达，伴随着肝内 Shh 和 yap1 信号的激活。此外，给予 Gant61 可改善肝再生，抑制肝内胆管反应，并降低 Shh 和 yap1 信号活性。因此，Shh-Yap1 信号似乎在 CCl 诱导的肝损伤中胆管反应细胞的增殖中发挥整体作用。这项研究应能增进我们对 CCl 诱导的肝损伤和胆管反应机制的理解，并为未来的肝病治疗研究提供支持。
