Shh-Yap signaling controls hepatic ductular reactions in CCl4 -induced liver injury.

Abstract

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.

• Authors: Lifang Jin, Huarong Huang, Jian Ni, Jiayuan Shen, Zuping Liu, Lijing Li, Shengmin Fu, Junyan Yan, Baowei Hu
• Journal: Environmental toxicology (Environ Toxicol) Vol. 36 Issue 2 Pg. 194-203 (Feb 2021) ISSN: 1522-7278 [Electronic] United States
• PMID: 32996673 (Publication Type: Journal Article)
• Copyright: © 2020 Wiley Periodicals LLC.

Chemical References

• Adaptor Proteins, Signal Transducing
• Cell Cycle Proteins
• GANT 61
• Hedgehog Proteins
• Pyridines
• Pyrimidines
• Shh protein, mouse
• YAP-Signaling Proteins
• Yap1 protein, mouse
• Carbon Tetrachloride

Topics

• Adaptor Proteins, Signal Transducing (antagonists & inhibitors, genetics, metabolism)
• Animals
• Carbon Tetrachloride (toxicity)
• Cell Cycle Proteins (antagonists & inhibitors, genetics, metabolism)
• Chemical and Drug Induced Liver Injury, Chronic (etiology, metabolism, pathology)
• Hedgehog Proteins (antagonists & inhibitors, genetics, metabolism)
• Hepatic Duct, Common (metabolism, pathology)
• Hepatocytes (metabolism, pathology)
• Male
• Mice
• Pyridines (pharmacology)
• Pyrimidines (pharmacology)
• Signal Transduction
• YAP-Signaling Proteins