The Non-Steroidal FXR Agonist Cilofexor Improves Portal Hypertension and Reduces Hepatic Fibrosis in a Rat NASH Model
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 NA...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
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MDPI AG
2021-01-01
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| Series: | Biomedicines |
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| Online Access: | https://www.mdpi.com/2227-9059/9/1/60 |
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| author | Philipp Schwabl Eva Hambruch Grant R. Budas Paul Supper Michael Burnet John T. Liles Manfred Birkel Ksenia Brusilovskaya Philipp Königshofer Markus Peck-Radosavljevic William J. Watkins Michael Trauner David G. Breckenridge Claus Kremoser Thomas Reiberger |
| author_facet | Philipp Schwabl Eva Hambruch Grant R. Budas Paul Supper Michael Burnet John T. Liles Manfred Birkel Ksenia Brusilovskaya Philipp Königshofer Markus Peck-Radosavljevic William J. Watkins Michael Trauner David G. Breckenridge Claus Kremoser Thomas Reiberger |
| author_sort | Philipp Schwabl |
| collection | DOAJ |
| description | 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 <i>shp, cyp7a1</i> and <i>fgf15</i> 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 <i>col1a1</i> (−37%) and <i>pdgfr-β</i> (−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; <i>p</i> = 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. |
| first_indexed | 2024-03-09T05:21:56Z |
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| institution | Directory Open Access Journal |
| issn | 2227-9059 |
| language | English |
| last_indexed | 2024-03-09T05:21:56Z |
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| series | Biomedicines |
| spelling | doaj.art-2fd79bb2ed77480192c227cb6828b2ed2023-12-03T12:39:33ZengMDPI AGBiomedicines2227-90592021-01-01916010.3390/biomedicines9010060The Non-Steroidal FXR Agonist Cilofexor Improves Portal Hypertension and Reduces Hepatic Fibrosis in a Rat NASH ModelPhilipp Schwabl0Eva Hambruch1Grant R. Budas2Paul Supper3Michael Burnet4John T. Liles5Manfred Birkel6Ksenia Brusilovskaya7Philipp Königshofer8Markus Peck-Radosavljevic9William J. Watkins10Michael Trauner11David G. Breckenridge12Claus Kremoser13Thomas Reiberger14Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, 1090 Vienna, AustriaPhenex Pharmaceuticals AG, 69123 Heidelberg, GermanyGilead Sciences Inc., Foster City, CA 94404, USADivision of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, 1090 Vienna, AustriaSynovo GmbH, 72076 Tübingen, GermanyGilead Sciences Inc., Foster City, CA 94404, USAPhenex Pharmaceuticals AG, 69123 Heidelberg, GermanyDivision of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, 1090 Vienna, AustriaDivision of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, 1090 Vienna, AustriaDivision of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, 1090 Vienna, AustriaGilead Sciences Inc., Foster City, CA 94404, USADivision of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, 1090 Vienna, AustriaGilead Sciences Inc., Foster City, CA 94404, USAPhenex Pharmaceuticals AG, 69123 Heidelberg, GermanyDivision of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, 1090 Vienna, AustriaBackground: 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 <i>shp, cyp7a1</i> and <i>fgf15</i> 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 <i>col1a1</i> (−37%) and <i>pdgfr-β</i> (−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; <i>p</i> = 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.https://www.mdpi.com/2227-9059/9/1/60NASHFXRcilofexorportal hypertensionfibrosisrats |
| spellingShingle | Philipp Schwabl Eva Hambruch Grant R. Budas Paul Supper Michael Burnet John T. Liles Manfred Birkel Ksenia Brusilovskaya Philipp Königshofer Markus Peck-Radosavljevic William J. Watkins Michael Trauner David G. Breckenridge Claus Kremoser Thomas Reiberger The Non-Steroidal FXR Agonist Cilofexor Improves Portal Hypertension and Reduces Hepatic Fibrosis in a Rat NASH Model Biomedicines NASH FXR cilofexor portal hypertension fibrosis rats |
| title | The Non-Steroidal FXR Agonist Cilofexor Improves Portal Hypertension and Reduces Hepatic Fibrosis in a Rat NASH Model |
| title_full | The Non-Steroidal FXR Agonist Cilofexor Improves Portal Hypertension and Reduces Hepatic Fibrosis in a Rat NASH Model |
| title_fullStr | The Non-Steroidal FXR Agonist Cilofexor Improves Portal Hypertension and Reduces Hepatic Fibrosis in a Rat NASH Model |
| title_full_unstemmed | The Non-Steroidal FXR Agonist Cilofexor Improves Portal Hypertension and Reduces Hepatic Fibrosis in a Rat NASH Model |
| title_short | The Non-Steroidal FXR Agonist Cilofexor Improves Portal Hypertension and Reduces Hepatic Fibrosis in a Rat NASH Model |
| title_sort | non steroidal fxr agonist cilofexor improves portal hypertension and reduces hepatic fibrosis in a rat nash model |
| topic | NASH FXR cilofexor portal hypertension fibrosis rats |
| url | https://www.mdpi.com/2227-9059/9/1/60 |
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