The FXR agonist PX20606 reduces liver damage, fibrosis and portal hypertension in cirrhotic rats

P Schwabl; E Hambruch; BA Payer; TL Schubert; B Strobel; S Fida; M Wagner; L Garnys; M Trauner; M Peck-Radosavljevic; C Kremoser; T Reiberger

doi:10.1055/s-0035-1551790

Zeitschrift für Gastroenterologie, Inhaltsverzeichnis

The FXR agonist PX20606 reduces liver damage, fibrosis and portal hypertension in cirrhotic rats

P Schwabl ¹, E Hambruch ², BA Payer ¹, TL Schubert ¹, B Strobel ¹, S Fida ¹, M Wagner ¹, L Garnys ¹, M Trauner ¹, M Peck-Radosavljevic ¹, C Kremoser ², T Reiberger ¹

¹Division of Gastroenterology & Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
²Phenex Pharmaceuticals AG, Heidelberg, Germany

Abstract

Background: FXR agonism attenuates liver injury and cholestatic and metabolic liver disease. We tested the impact of the synthetic FXR agonist PX20606 (PX) on liver histology, inflammation and hemodynamics in a rodent model of toxic cirrhosis.

Methods: Cirrhosis was induced by carbontetrachloride (CCl4) administration for 12 weeks in Sprague Dawley rats. Controls received corn-oil. PX (10 mg/kg/day) or placebo were gavaged daily from week 4. Blood was sampled at week 11. After 12 weeks, mean arterial pressure (MAP), heart rate (HR), portal pressure (PP) and superior mesenteric artery blood flow (SMABF) were measured. Liver fibrosis was assessed by Sirius Red area (SRA) and content of hydroxyproline (HP), collagen-I (Col1) and α-smooth muscle actin (αSMA). Expression of fibrogenic genes was quantified by qRT-PCR.

Results: CCl4 rats presented with marked cirrhosis, elevated transaminases and portal hypertension. In CCl4 rats, PX treatment significantly ameliorated fibrosis (SRA: 6.99 ± 3.15 vs. 3.97 ± 1.64%; p < 0.001 HP: 415 ± 86 vs. 134 ± 14 µg/g; p = 0.002) and reduced Col1 (12.28 ± 1.78 vs. 4.93 ± 0.28; p < 0.05) and αSMA (7.78 ± 1.41 vs. 2.08 ± 0.49; p < 0.05) expression. Accordingly AST (555 ± 30 vs. 227 ± 83 IU/ml; p < 0.001) and ALT (538 ± 233 vs. 193 ± 86 IU/ml; p = 0.008) significantly decreased under PX treatment, while plasma cholesterol and triglycerides levels remained unaffected. PX treatment significantly decreased PP (11.9 ± 1.4 vs. 9.7 ± 1.4 mmHg; p = 0.037) and increased SMABF (8.88 ± 2.62 vs. 13.81 ± 2.81 ml/min/100 g; p = 0.021), while not affecting MAP (125 ± 14 vs. 116 ± 25 mmHg) nor HR (330 ± 29 vs. 333 ± 52bpm). Livers of CCl4-PX rats significantly overexpressed FXR target genes including bile salt export pump (2.5 x), small heterodimer partner (2.3 x), cystathionase (2.1 x) and dimethylargininase (1.7 x). Gene expression of endothelin-1 (0.45), PDGF-Rβ (0.51 x) and αSMA (0.61 x) was significantly reduced.

Conclusions: PX20606 treatment effectively reduces hepatic inflammation, fibrogenesis and portal pressure in cirrhotic rats.