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 countera...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2023-11-01
|
| Series: | JHEP Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589555923002057 |
| _version_ | 1827781689232850944 |
|---|---|
| author | Claudia D. Fuchs Natalie Sroda Hubert Scharnagl Ruchi Gupta Wesley Minto Tatjana Stojakovic John T. Liles Grant Budas David Hollenback Michael Trauner |
| author_facet | Claudia D. Fuchs Natalie Sroda Hubert Scharnagl Ruchi Gupta Wesley Minto Tatjana Stojakovic John T. Liles Grant Budas David Hollenback Michael Trauner |
| author_sort | Claudia D. Fuchs |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T15:22:14Z |
| format | Article |
| id | doaj.art-98d4075a323d4c7285415bf45d052aaa |
| institution | Directory Open Access Journal |
| issn | 2589-5559 |
| language | English |
| last_indexed | 2024-03-11T15:22:14Z |
| publishDate | 2023-11-01 |
| publisher | Elsevier |
| record_format | Article |
| series | JHEP Reports |
| spelling | doaj.art-98d4075a323d4c7285415bf45d052aaa2023-10-28T05:09:33ZengElsevierJHEP Reports2589-55592023-11-01511100874Non-steroidal FXR agonist cilofexor improves cholestatic liver injury in the Mdr2-/- mouse model of sclerosing cholangitisClaudia D. Fuchs0Natalie Sroda1Hubert Scharnagl2Ruchi Gupta3Wesley Minto4Tatjana Stojakovic5John T. Liles6Grant Budas7David Hollenback8Michael Trauner9Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, AustriaGilead Sciences, Inc., Foster City, CA, USAClinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, AustriaGilead Sciences, Inc., Foster City, CA, USAGilead Sciences, Inc., Foster City, CA, USAClinical Institute of Medical and Chemical Laboratory Diagnostics, University Hospital Graz, AustriaGilead Sciences, Inc., Foster City, CA, USAGilead Sciences, Inc., Foster City, CA, USAGilead Sciences, Inc., Foster City, CA, USAHans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Austria; Corresponding author. Address: Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria; Tel.: +43 1 40 40047410.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.http://www.sciencedirect.com/science/article/pii/S2589555923002057Bile acid signalingInflammation FibrosisFXR, FGF15/19 Bile acid metabolism |
| spellingShingle | Claudia D. Fuchs Natalie Sroda Hubert Scharnagl Ruchi Gupta Wesley Minto Tatjana Stojakovic John T. Liles Grant Budas David Hollenback Michael Trauner Non-steroidal FXR agonist cilofexor improves cholestatic liver injury in the Mdr2-/- mouse model of sclerosing cholangitis JHEP Reports Bile acid signaling Inflammation Fibrosis FXR, FGF15/19 Bile acid metabolism |
| title | Non-steroidal FXR agonist cilofexor improves cholestatic liver injury in the Mdr2-/- mouse model of sclerosing cholangitis |
| title_full | Non-steroidal FXR agonist cilofexor improves cholestatic liver injury in the Mdr2-/- mouse model of sclerosing cholangitis |
| title_fullStr | Non-steroidal FXR agonist cilofexor improves cholestatic liver injury in the Mdr2-/- mouse model of sclerosing cholangitis |
| title_full_unstemmed | Non-steroidal FXR agonist cilofexor improves cholestatic liver injury in the Mdr2-/- mouse model of sclerosing cholangitis |
| title_short | Non-steroidal FXR agonist cilofexor improves cholestatic liver injury in the Mdr2-/- mouse model of sclerosing cholangitis |
| title_sort | non steroidal fxr agonist cilofexor improves cholestatic liver injury in the mdr2 mouse model of sclerosing cholangitis |
| topic | Bile acid signaling Inflammation Fibrosis FXR, FGF15/19 Bile acid metabolism |
| url | http://www.sciencedirect.com/science/article/pii/S2589555923002057 |
| work_keys_str_mv | AT claudiadfuchs nonsteroidalfxragonistcilofexorimprovescholestaticliverinjuryinthemdr2mousemodelofsclerosingcholangitis AT nataliesroda nonsteroidalfxragonistcilofexorimprovescholestaticliverinjuryinthemdr2mousemodelofsclerosingcholangitis AT hubertscharnagl nonsteroidalfxragonistcilofexorimprovescholestaticliverinjuryinthemdr2mousemodelofsclerosingcholangitis AT ruchigupta nonsteroidalfxragonistcilofexorimprovescholestaticliverinjuryinthemdr2mousemodelofsclerosingcholangitis AT wesleyminto nonsteroidalfxragonistcilofexorimprovescholestaticliverinjuryinthemdr2mousemodelofsclerosingcholangitis AT tatjanastojakovic nonsteroidalfxragonistcilofexorimprovescholestaticliverinjuryinthemdr2mousemodelofsclerosingcholangitis AT johntliles nonsteroidalfxragonistcilofexorimprovescholestaticliverinjuryinthemdr2mousemodelofsclerosingcholangitis AT grantbudas nonsteroidalfxragonistcilofexorimprovescholestaticliverinjuryinthemdr2mousemodelofsclerosingcholangitis AT davidhollenback nonsteroidalfxragonistcilofexorimprovescholestaticliverinjuryinthemdr2mousemodelofsclerosingcholangitis AT michaeltrauner nonsteroidalfxragonistcilofexorimprovescholestaticliverinjuryinthemdr2mousemodelofsclerosingcholangitis |