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