Non-steroidal FXR agonist cilofexor improves cholestatic liver injury in the Mdr2(-/-) mouse model of sclerosing cholangitis

BACKGROUND & AIMS: The nuclear receptor farnesoid X receptor (FXR) is a key regulator of hepatic bile acid (BA) and lipid metabolism, inflammation and fibrosis. Here, we aimed to explore the potential of cilofexor (GS-9674), a non-steroidal FXR agonist, as a therapeutic approach for counteractin...

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Detalles Bibliográficos
Autores principales: Fuchs, Claudia D., Sroda, Natalie, Scharnagl, Hubert, Gupta, Ruchi, Minto, Wesley, Stojakovic, Tatjana, Liles, John T., Budas, Grant, Hollenback, David, Trauner, Michael
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2023
Materias:
Research Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10568427/
https://www.ncbi.nlm.nih.gov/pubmed/37841639
http://dx.doi.org/10.1016/j.jhepr.2023.100874
Descripción
Sumario:BACKGROUND & AIMS: The nuclear receptor farnesoid X receptor (FXR) is a key regulator of hepatic bile acid (BA) and lipid metabolism, inflammation and fibrosis. Here, we aimed to explore the potential of cilofexor (GS-9674), a non-steroidal FXR agonist, as a therapeutic approach for counteracting features of cholestatic liver injury by evaluating its efficacy and mechanisms in the Mdr2/Abcb4 knockout ((-/-)) mouse model of sclerosing cholangitis. METHODS: FVB/N wild-type and Mdr2(-/-) or BALB/c wild-type and Mdr2(-/-) mice were treated with 0, 10, 30 or 90 mg/kg cilofexor by gavage every 24 h for 10 weeks. Serum biochemistry, gene expression profile, hydroxyproline content, and picrosirius red and F4/80 immunostaining, were investigated. Bile flow, biliary bicarbonate and BA output, and hepatic BA profile, were assessed. RESULTS: Cilofexor treatment improved serum levels of aspartate aminotransferase, alkaline phosphatase as well as BAs in Mdr2(-/-) animals. Hepatic fibrosis was improved, as reflected by the reduced picrosirius red-positive area and hydroxyproline content in liver sections of cilofexor-treated Mdr2(-/-) mice. Intrahepatic BA concentrations were lowered in cilofexor-treated Mdr2(-/-) mice, while hepatobiliary bile flow and bicarbonate output were increased. CONCLUSION: Collectively the current data show that cilofexor treatment improves cholestatic liver injury and decreases hepatic fibrosis in the Mdr2(-/-) mouse model of sclerosing cholangitis. IMPACT AND IMPLICATIONS: Treatment with cilofexor, a non-steroidal farnesoid X receptor (FXR) agonist, improved histological features of sclerosing cholangitis, cholestasis and hepatic fibrosis in the Mdr2(-/-) mouse model. These findings indicate, that pharmacological stimulation of intestinal FXR-mediated gut-liver signaling, via fibroblast growth factor 15 (thereby reducing bile acid synthesis), may be sufficient to attenuate cholestatic liver injury in the Mdr2(-/-) mouse model of sclerosing cholangitis, thus arguing for potential therapeutic properties of cilofexor in cholestatic liver diseases.

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