As an intercellular signaling molecule, Hedgehog (Hh) plays a critical role in liver fibrosis/regeneration. Transcription effectors Gli1 and Gli2 are key components of the Hh signaling pathway. However, whether inhibition of Gli1/2 activity can affect liver fibrogenesis is largely unknown. In the present study, we investigated the effect of Gant61 (a Gli1/2 transcription factor inhibitor) on liver fibrosis and its possible mechanism. Wild-type and Shh-EGFP-Cre male mice were exposed to CCl4, and then treated with or without Gant61 for four weeks. The level of liver injury/fibrosis and expression levels of mRNA and protein related to the Hh ligand/pathway were assessed. In our study, CCl4 treatment induced liver injury/fibrosis and promoted activation of hepatic stellate cells (HSCs). In addition, CCl4 induced the expression of Shh ligands in and around the fibrotic lesion, accompanied by induction of mRNA and protein expression of Hh components (Smo, Gli1 and Gli2). However, administration of Gant61 decreased liver fibrosis by reduction in HSC number, down-regulation of mRNA and protein expression of Hh components (Smo, Gli1 and Gli2), and cell-cycle arrest of HSCs. Our data highlight the importance of the Shh pathway for the development of liver fibrosis, and also suggest Glis as potential therapeutic targets for the treatment of liver fibrosis.

中文翻译：

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Gant61通过抑制Hedgehog信号传导活性改善了CCl4诱导的肝纤维化。

刺猬（Hh）作为一种细胞间信号分子，在肝纤维化/再生中起着至关重要的作用。转录效应子Gli1和Gli2是Hh信号通路的关键组成部分。但是，对Gli1 / 2活性的抑制是否会影响肝纤维化尚不清楚。在本研究中，我们研究了Gant61（一种Gli1 / 2转录因子抑制剂）对肝纤维化的作用及其可能的机制。将野生型和Shh-EGFP-Cre雄性小鼠暴露于CCl4，然后在有或没有Gant61的情况下处理四周。评估肝损伤/纤维化水平以及与Hh配体/途径相关的mRNA和蛋白质的表达水平。在我们的研究中，CCl4处理可诱导肝损伤/纤维化并促进肝星状细胞（HSC）的活化。此外，CCl4诱导纤维化病变内和周围的Shh配体表达，同时诱导Hh成分（Smo，Gli1和Gli2）的mRNA和蛋白质表达。然而，施用Gant61可通过减少HSC数量，下调Hh成分（Smo，Gli1和Gli2）的mRNA和蛋白表达以及抑制HSC的细胞周期来减少肝纤维化。我们的数据突出了Shh途径对肝纤维化发展的重要性，也暗示了Glis作为治疗肝纤维化的潜在治疗靶标。和HSC的细胞周期阻滞。我们的数据突出了Shh途径对肝纤维化发展的重要性，也暗示了Glis作为治疗肝纤维化的潜在治疗靶标。和HSC的细胞周期阻滞。我们的数据突出了Shh途径对肝纤维化发展的重要性，也暗示了Glis作为治疗肝纤维化的潜在治疗靶标。