Carbon tetrachloride (CCl4) 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 CCl4‐treated livers and the possible mechanisms. Wild‐type and Shh‐EGFP‐Cre male mice were exposed to CCl4 (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 CCl4 treatment induced liver injury and promoted activation and proliferation of ductular reaction cells. In addition, CCl4 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 CCl4‐induced liver injury. This study should improve our understanding of the mechanism of CCl4‐induced liver injury and ductular reactions and provide support for future investigations on liver disease therapy.

中文翻译：

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Shh-Yap 信号传导控制 CCl 4 诱导的肝损伤中的肝小管反应

四氯化碳 (CCl4) 暴露可诱发肝小管反应。然而，迄今为止，相关机制在很大程度上仍然未知。声波刺猬 (Shh) 和 Yes 相关蛋白 (Yap) 信号与肝损伤和再生相关。在此，我们研究了 Shh 和 Yap 信号在 CCl4 处理的肝脏中导管反应细胞命运中的作用以及可能的机制。将野生型和 Shh-EGFP-Cre 雄性小鼠暴露于 CCl4 (2 mL/kg)，然后用或不用 Shh 信号抑制剂 Gant61 进行处理。评估了肝损伤水平、小管反应细胞的增殖以及与 Shh 和 Yap 信号成分相关的 mRNA 和蛋白质的表达水平。结果表明，四氯化碳处理可诱导肝损伤并促进小管反应细胞的活化和增殖。此外，CCl4 诱导肝细胞中 Shh 配体的表达，伴随着肝脏中 Shh 和 Yap1 信号的激活。此外，Gant61 的给药改善了肝脏再生，抑制了肝小管反应，并降低了 Shh 和 Yap1 信号活性。因此，Shh-Yap1 信号似乎在 CCl4 诱导的肝损伤中导管反应细胞的增殖中起着不可或缺的作用。本研究应提高我们对四氯化碳引起的肝损伤和小管反应机制的理解，并为未来肝病治疗的研究提供支持。并降低 Shh 和 Yap1 信号活动。因此，Shh-Yap1 信号似乎在 CCl4 诱导的肝损伤中导管反应细胞的增殖中起着不可或缺的作用。本研究应提高我们对四氯化碳引起的肝损伤和小管反应机制的理解，并为未来肝病治疗的研究提供支持。并降低 Shh 和 Yap1 信号活动。因此，Shh-Yap1 信号似乎在 CCl4 诱导的肝损伤中导管反应细胞的增殖中起着不可或缺的作用。本研究应提高我们对四氯化碳引起的肝损伤和小管反应机制的理解，并为未来肝病治疗的研究提供支持。