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

BackgroundThe nuclear receptor farnesoid X (FXR) is a key regulator of hepatic BA and lipid metabolism, inflammation fibrosis. Here, we aimed to explore the potential cilofexor, non-steroidal FXR agonist, as therapeutic approach for counteracting features cholestatic liver injury by evaluating efficacy mechanisms in Mdr2/Abcb4 knockout (-/-) mouse model sclerosing cholangitis.MethodsFVB/N WT Mdr2-/- or BALB/c mice were treated with 0, 10, 30 90 mg/kg cilofexor gavage every 24h 10 weeks. Serum biochemistry, gene expression profile, hydroxyproline measurement well picrosirius red (PSR) F4/80 immunostaining investigated. Bile flow biliary bicarbonate bile acid (BA) output profile assessed.ResultsCilofexor treatment improved serum levels AST, ALP BAs animals. Hepatic fibrosis was reflected reduction PSR positive area sections content mice. Intrahepatic concentrations lowered mice, while hepatobiliary increased.ConclusionCollectively current data show that improves decreases cholangitis.Impact ImplicationTreatment histological cholangitis, cholestasis fibrosis, indicating pharmacological stimulation intestinal gut-liver signaling via FGF15 (thereby reducing synthesis) may be sufficient attenuate cholangitis.