The Non-Steroidal FXR Agonist Cilofexor Improves Portal Hypertension and Reduces Hepatic Fibrosis in a Rat NASH Model
| العنوان: | The Non-Steroidal FXR Agonist Cilofexor Improves Portal Hypertension and Reduces Hepatic Fibrosis in a Rat NASH Model |
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| المؤلفون: | Markus Peck-Radosavljevic, William J. Watkins, John T. Liles, Thomas Reiberger, Grant R. Budas, Ksenia Brusilovskaya, Eva Hambruch, Philipp Schwabl, Michael Burnet, Claus Kremoser, David G. Breckenridge, Philipp Königshofer, Manfred Birkel, Michael Trauner, P Supper |
| المصدر: | Biomedicines Volume 9 Issue 1 Biomedicines, Vol 9, Iss 60, p 60 (2021) |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | 0301 basic medicine, Mean arterial pressure, medicine.medical_specialty, Cirrhosis, Portal venous pressure, Medicine (miscellaneous), Propranolol, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, 0302 clinical medicine, Fibrosis, Internal medicine, NAFLD, cilofexor, Medicine, propranolol, lcsh:QH301-705.5, business.industry, cirrhosis, fibrosis, NASH, portal hypertension, medicine.disease, rats, 030104 developmental biology, Endocrinology, lcsh:Biology (General), FXR, Portal hypertension, 030211 gastroenterology & hepatology, Steatohepatitis, business, Hepatic fibrosis, farnesoid X receptor, medicine.drug |
| الوصف: | 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 &minus 41% (10 mg/kg) and &minus 69% (30 mg/kg), respectively. The 30 mg/kg cilofexor dose significantly reduced hepatic hydroxyproline content (&minus 41%), expression of col1a1 (&minus 37%) and pdgfr-&beta (&minus 36%), as well as desmin area (&minus 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 (&minus 28%) but also mean arterial pressure (&minus 25%) and heart rate (&minus 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. |
| وصف الملف: | application/pdf |
| تدمد: | 2227-9059 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::4a092db3be3feda7def92ef951fb9c5e https://pubmed.ncbi.nlm.nih.gov/33435509 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....4a092db3be3feda7def92ef951fb9c5e |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 22279059 |
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