Philipp Schwabl1,2,3, Eva Hambruch4, Grant R Budas5, Paul Supper1,2, Michael Burnet6, John T Liles5, Manfred Birkel4, Ksenia Brusilovskaya1,2,3, Philipp Königshofer1,2,3, Markus Peck-Radosavljevic1,2,7, William J Watkins5, Michael Trauner1, David G Breckenridge5, Claus Kremoser4, Thomas Reiberger1,2,3,8,9. 1. Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, 1090 Vienna, Austria. 2. Vienna Hepatic Experimental Hemodynamic (HEPEX) Laboratory, Medical University of Vienna, 1090 Vienna, Austria. 3. Christian Doppler Lab for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, 1090 Vienna, Austria. 4. Phenex Pharmaceuticals AG, 69123 Heidelberg, Germany. 5. Gilead Sciences Inc., Foster City, CA 94404, USA. 6. Synovo GmbH, 72076 Tübingen, Germany. 7. Department of Internal Medicine and Gastroenterology (IMuG), Hepatology, Endocrinology, Rheumatology, and Nephrology with Centralized Emergency Service (ZAE), Klinikum Klagenfurt am Wörthersee, 9020 Klagenfurt, Austria. 8. Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases (LBI-RUD), 1090 Vienna, Austria. 9. CeMM Research Center for Molecular Medicine, The Austrian Academy of Sciences, 1090 Vienna, Austria.
Abstract
BACKGROUND: The farnesoid X receptor (FXR) influences hepatic metabolism, inflammation and liver fibrosis as key components of non-alcoholic steatohepatitis (NASH). We studied the effects of the non-steroidal FXR agonist cilofexor (formerly GS-9674) on portal pressure and fibrosis in experimental NASH. METHODS: NASH was induced in Wistar rats using a choline-deficient high-fat diet plus intraperitoneal sodium nitrite injections. First, a dose-finding study was performed with 10 mg/kg and 30 mg/kg of cilofexor, focusing on histological readouts. Liver fibrosis was assessed by Picro-Sirius-Red, desmin staining and hepatic hydroxyproline content. Gene expression was determined by RT-PCR. In a subsequent hemodynamic study, rats received 30 mg/kg cilofexor with or without propranolol (25 mg/kg). Portal pressure, systemic hemodynamics and splanchnic blood flow were measured. RESULTS: Cilofexor dose-dependently induced FXR target genes shp, cyp7a1 and fgf15 in hepatic and ileal tissues, paralleled by a dose-dependent reduction in liver fibrosis area (Picro-Sirius-Red) of -41% (10 mg/kg) and -69% (30 mg/kg), respectively. The 30 mg/kg cilofexor dose significantly reduced hepatic hydroxyproline content (-41%), expression of col1a1 (-37%) and pdgfr-β (-36%), as well as desmin area (-42%) in NASH rats. Importantly, cilofexor decreased portal pressure (11.9 ± 2.1 vs. 8.9 ± 2.2 mmHg; p = 0.020) without affecting splanchnic blood-flow or systemic hemodynamics. The addition of propranolol to cilofexor additionally reduced splanchnic inflow (-28%) but also mean arterial pressure (-25%) and heart rate (-37%). CONCLUSION: The non-steroidal FXR agonist cilofexor decreased portal hypertension and reduced liver fibrosis in NASH rats. While cilofexor seems to primarily decrease sinusoidal resistance in cirrhotic portal hypertension, the combination with propranolol additionally reduced mesenteric hyperperfusion.
BACKGROUND: The farnesoid X receptor (FXR) influences hepatic metabolism, inflammation and liver fibrosis as key components of non-alcoholic steatohepatitis (NASH). We studied the effects of the non-steroidal FXR agonist cilofexor (formerly GS-9674) on portal pressure and fibrosis in experimental NASH. METHODS: NASH was induced in Wistar rats using a choline-deficient high-fat diet plus intraperitoneal sodium nitrite injections. First, a dose-finding study was performed with 10 mg/kg and 30 mg/kg of cilofexor, focusing on histological readouts. Liver fibrosis was assessed by Picro-Sirius-Red, desmin staining and hepatic hydroxyproline content. Gene expression was determined by RT-PCR. In a subsequent hemodynamic study, rats received 30 mg/kg cilofexor with or without propranolol (25 mg/kg). Portal pressure, systemic hemodynamics and splanchnic blood flow were measured. RESULTS:Cilofexor dose-dependently induced FXR target genes shp, cyp7a1 and fgf15 in hepatic and ileal tissues, paralleled by a dose-dependent reduction in liver fibrosis area (Picro-Sirius-Red) of -41% (10 mg/kg) and -69% (30 mg/kg), respectively. The 30 mg/kg cilofexor dose significantly reduced hepatic hydroxyproline content (-41%), expression of col1a1 (-37%) and pdgfr-β (-36%), as well as desmin area (-42%) in NASH rats. Importantly, cilofexor decreased portal pressure (11.9 ± 2.1 vs. 8.9 ± 2.2 mmHg; p = 0.020) without affecting splanchnic blood-flow or systemic hemodynamics. The addition of propranolol to cilofexor additionally reduced splanchnic inflow (-28%) but also mean arterial pressure (-25%) and heart rate (-37%). CONCLUSION: The non-steroidal FXR agonist cilofexor decreased portal hypertension and reduced liver fibrosis in NASH rats. While cilofexor seems to primarily decrease sinusoidal resistance in cirrhotic portal hypertension, the combination with propranolol additionally reduced mesenteric hyperperfusion.
Authors: Stefan Traussnigg; Christian Kienbacher; Emina Halilbasic; Christian Rechling; Lili Kazemi-Shirazi; Harald Hofer; Petra Munda; Michael Trauner Journal: Dig Dis Date: 2015-07-06 Impact factor: 2.404
Authors: Zobair M Younossi; Vlad Ratziu; Rohit Loomba; Mary Rinella; Quentin M Anstee; Zachary Goodman; Pierre Bedossa; Andreas Geier; Susanne Beckebaum; Philip N Newsome; David Sheridan; Muhammad Y Sheikh; James Trotter; Whitfield Knapple; Eric Lawitz; Manal F Abdelmalek; Kris V Kowdley; Aldo J Montano-Loza; Jerome Boursier; Philippe Mathurin; Elisabetta Bugianesi; Giuseppe Mazzella; Antonio Olveira; Helena Cortez-Pinto; Isabel Graupera; David Orr; Lise Lotte Gluud; Jean-Francois Dufour; David Shapiro; Jason Campagna; Luna Zaru; Leigh MacConell; Reshma Shringarpure; Stephen Harrison; Arun J Sanyal Journal: Lancet Date: 2019-12-05 Impact factor: 79.321