Gant61 ameliorates CCl4-induced liver fibrosis by inhibition of Hedgehog signaling activity.

Abstract

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.

• Authors: Shen Jiayuan, Yan Junyan, Wei Xiangzhen, Liu Zuping, Ni Jian, Hu Baowei, Jin Lifang
• Journal: Toxicology and applied pharmacology (Toxicol Appl Pharmacol) Vol. 387 Pg. 114853 (01 15 2020) ISSN: 1096-0333 [Electronic] United States
• PMID: 31816328 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019. Published by Elsevier Inc.

Chemical References

• GANT 61
• Gli1 protein, mouse
• Gli2 protein, mouse
• Hedgehog Proteins
• Pyridines
• Pyrimidines
• Smo protein, mouse
• Smoothened Receptor
• Zinc Finger Protein GLI1
• Zinc Finger Protein Gli2
• Carbon Tetrachloride

Topics

• Animals
• Carbon Tetrachloride (toxicity)
• Down-Regulation (drug effects)
• Hedgehog Proteins (metabolism)
• Humans
• Liver (drug effects, pathology)
• Liver Cirrhosis, Experimental (chemically induced, drug therapy, pathology)
• Male
• Mice
• Pyridines (pharmacology, therapeutic use)
• Pyrimidines (pharmacology, therapeutic use)
• Signal Transduction (drug effects)
• Smoothened Receptor (metabolism)
• Zinc Finger Protein GLI1 (antagonists & inhibitors, metabolism)
• Zinc Finger Protein Gli2 (antagonists & inhibitors, metabolism)