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.

Yap signalling regulates ductular reactions in mice with CRISPR/Cas9-induced glycogen storage disease type Ia

“…Previous studies have shown that Yap signalling activity is positively correlated with the activation of ductular reactions (Jin et al 2021 ). As such, we explored Yap signalling pathway activity and target gene expression levels in the livers of 18–20-day-old G6pc −/− and WT mice.…”

The Protective Effect of Lycium barbarum Betaine and Effervescent Tablet Against Carbon Tetrachloride-Induced Acute Liver Injury in Rats

“…CCl 4 contamination in the environment can be absorbed by the body. 33 The purpose of this study was to investigate the protective effect of LBB and LBBET against CCl 4 -induced liver injury. In this study, it was confirmed that liver damage caused by CCl 4 can be remarkably alleviated by using LBB and LBBET as raw materials.…”

Knockdown of Yap attenuates TAA-induced hepatic fibrosis by interaction with hedgehog signals

“…The Hh pathway was recently shown to control the activity of YAP in HSCs, and blocking Hh pathway and YAP activation prevented HSCs transdifferentiating into MF (Du et al 2018). Furthermore, the cross talking between Shh and Yap signaling are correlated with liver injury and Yap is known to be a downstream effect of the Shh pathway in fibrotic livers (Jin et al 2021). Liver injury triggers the activation of the Hh pathway and Yap, both of which switch from typical low or absent expression levels to high activities (Liu et al 2019; Swiderska‐Syn et al 2016).…”