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GSK805 inhibits alpha-smooth muscle expression and modulates liver inflammation without impairing the well-being of
Wiebke-Felicitas Nierath1, Emily Leitner1, Sabrina Reimann1
1Rudolf-Zenker-Institute of Experimental Surgery, Rostock University Medical Center, Rostock, Germany.
Abstract:
Cholestatic liver diseases, such as primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), lead to inflammation and severe hepatic damage with limited therapeutic options. This study assessed the efficacy of the inverse RORγt agonist, GSK805, both in vitro using the hepatic stellate cell-line LX-2 and in vivo using male bile duct-ligated BALB/c mice. In vitro, 0.3 μM GSK805 reduced alpha-smooth muscle actin expression in LX-2 cells. In vivo, GSK805 significantly decreased IL-23R, TNF-α, and IFN-γ expression in cholestatic liver. Despite high concentrations of GSK805 in the liver, no significant reduction in fibrosis was noticed. GSK805 significantly increased aspartate aminotransferase and alanine aminotransferase activity in the blood, while levels of glutamate dehydrogenase, alkaline phosphatase, and bilirubin were not substantially increased. Importantly, GSK805 did neither increase an animal distress score nor substantially reduce body weight, burrowing activity, or nesting behavior. These results suggest that a high liver concentration of GSK805 is achieved by daily oral administration and that this drug modulates inflammation in cholestatic mice without impairing animal well-being.
Insights
GSK805, an RORγt agonist, reduced inflammation markers in cholestatic liver disease models. While it modulated inflammation without harming animal well-being, it did not significantly reduce fibrosis or liver enzymes.
Area of Science:
- Hepatology
- Immunology
- Pharmacology
Background:
- Cholestatic liver diseases like primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) cause significant liver damage.
- Limited therapeutic options exist for these inflammatory liver conditions.
Purpose of the Study:
- To evaluate the efficacy of GSK805, an inverse RORγt agonist, in treating cholestatic liver diseases.
- To assess GSK805's effects on inflammation and fibrosis in vitro and in vivo models.
Main Methods:
- In vitro: LX-2 hepatic stellate cells treated with GSK805.
- In vivo: Male bile duct-ligated BALB/c mice treated with GSK805.
- Assessed alpha-smooth muscle actin, IL-23R, TNF-α, IFN-γ, fibrosis, liver enzymes, and animal well-being.
Main Results:
- GSK805 reduced alpha-smooth muscle actin in vitro.
- In vivo, GSK805 decreased IL-23R, TNF-α, and IFN-γ expression in cholestatic livers.
- No significant fibrosis reduction was observed; aspartate aminotransferase and alanine aminotransferase increased.
- Animal well-being, including body weight and behavior, was not substantially affected.
Conclusions:
- GSK805 achieves high liver concentrations via oral administration.
- The drug modulates inflammation in cholestatic liver disease models without compromising animal welfare.
- Further research is needed to address the lack of fibrosis reduction and enzyme changes.
