Non-steroidal FXR Agonist Cilofexor Improves Cholestatic Liver Injury in the Mouse Model of Sclerosing Cholangitis

Overview

Journal JHEP Rep

Specialty Gastroenterology

Date 2023 Oct 16

PMID 37841639

Authors

Claudia D Fuchs

Natalie Sroda

Hubert Scharnagl

Ruchi Gupta

Wesley Minto

Tatjana Stojakovic

John T Liles

Grant Budas

David Hollenback

Michael Trauner

Affiliations

Soon will be listed here.

Abstract

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 knockout () mouse model of sclerosing cholangitis.

Methods: FVB/N wild-type and or BALB/c wild-type and 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 animals. Hepatic fibrosis was improved, as reflected by the reduced picrosirius red-positive area and hydroxyproline content in liver sections of cilofexor-treated mice. Intrahepatic BA concentrations were lowered in cilofexor-treated 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 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 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 mouse model of sclerosing cholangitis, thus arguing for potential therapeutic properties of cilofexor in cholestatic liver diseases.

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