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REV-ERBα Agonist GSK4112 attenuates Fas-induced Acute Hepatic Damage in Mice
Ruyue Shao1,2, Yongqiang Yang3, Kerui Fan3
1Clinical Medical School, Chongqing Medical and Pharmaceutical College, Chongqing 401331, China.
Abstract:
Fas-induced apoptosis is a central mechanism of hepatocyte damage during acute and chronic hepatic disorders. Increasing evidence suggests that circadian clock plays critical roles in the regulation of cell fates. In the present study, the potential significance of REV-ERBα, a core ingredient of circadian clock, in Fas-induced acute liver injury has been investigated. The anti-Fas antibody Jo2 was injected intraperitoneally in mice to induce acute liver injury and the REV-ERBα agonist GSK4112 was administered. The results indicated that treatment of GSK4112 decreased the level of plasma ALT and AST, attenuated the liver histological changes, and promoted the survival rate in Jo2-insulted mice. Treatment with GSK4112 also downregulated the activities of caspase-3 and caspase-8, suppressed hepatocyte apoptosis. In addition, treatment with GSK4112 decreased the level of Fas and enhanced the phosphorylation of Akt. In conclusion, treatment with GSK4112 alleviated Fas-induced apoptotic liver damage in mice, suggesting that REV-ERBα agonist might have potential value in pharmacological intervention of Fas-associated liver injury.
Insights
REV-ERBα agonist GSK4112 protects against Fas-induced liver injury by reducing hepatocyte apoptosis. This finding suggests potential therapeutic value for REV-ERBα agonists in treating Fas-associated liver damage.
Area of Science:
- Hepatology
- Molecular Biology
- Chronobiology
Background:
- Fas-induced apoptosis is a key factor in liver damage during hepatic disorders.
- The circadian clock, including REV-ERBα, influences cell fate and may modulate liver injury.
- REV-ERBα's role in Fas-induced acute liver injury requires further investigation.
Purpose of the Study:
- To investigate the significance of REV-ERBα in Fas-induced acute liver injury.
- To evaluate the protective effects of the REV-ERBα agonist GSK4112 in a mouse model of liver injury.
Main Methods:
- Acute liver injury was induced in mice using an anti-Fas antibody (Jo2).
- Mice were treated with the REV-ERBα agonist GSK4112.
- Liver damage markers (ALT, AST), histological changes, hepatocyte apoptosis, caspase activity, Fas levels, and Akt phosphorylation were assessed.
Main Results:
- GSK4112 treatment reduced plasma ALT and AST levels and attenuated liver histological damage.
- The agonist promoted survival rates and suppressed hepatocyte apoptosis by downregulating caspase-3 and caspase-8 activity.
- GSK4112 decreased Fas levels and enhanced Akt phosphorylation in Jo2-insulted mice.
Conclusions:
- Treatment with GSK4112 effectively alleviated Fas-induced apoptotic liver damage in mice.
- REV-ERBα agonists demonstrate potential as a pharmacological intervention for Fas-associated liver injury.
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