The non-steroidal FXR agonists PX20606 and GS-9674 improve liver fibrosis and portal hypertension in rodent models of cholestatic, metabolic and toxic liver cirrhosis

T Reiberger; P Schwabl; P Supper; D Bauer; BA Payer; N Rohr-Udilova; B Podesser; C Kremoser; M Trauner

doi:10.1055/s-0036-1583977

Zeitschrift für Gastroenterologie, Table of Contents

The non-steroidal FXR agonists PX20606 and GS-9674 improve liver fibrosis and portal hypertension in rodent models of cholestatic, metabolic and toxic liver cirrhosis

T Reiberger ¹, P Schwabl ¹, P Supper ¹, D Bauer ¹, BA Payer ¹, N Rohr-Udilova ¹, B Podesser ¹, C Kremoser ², M Trauner ¹

¹General Hospital of Vienna, Vienna, Austria
²Phenex Pharmaceuticals AG, Heidelberg, Germany

Abstract

Background: FXR agonists show beneficial effects in cholestasis and NASH. We evaluated the non-steroidal FXR agonists PX20606 and GS-9674 in rodent models of toxic (CCl4), and metabolic (NASH) liver fibrosis.

Methods: Toxic model: CCl4 2x/week i.p. for 12weeks. PX20606 (10 mg/kg/day) was given from weeks4 – 12 of CCl4. NASH model: choline-deficient high-fat diet plus repeated NaNO2 (25 mg/kg i.p., 2x/week) for 10 weeks. GS-9674 (10 mg/kg/day or 30 mg/kg/day) was gavaged from weeks4 – 10, with/without propranolol (PROP, 25 mg/kg). At end of treatment, 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), content of hydroxyproline (HP). Hepatic gene expression was quantified by qRT-PCR.

Results: In CCl4 rats, PX treatment ameliorated fibrosis (SRA: 6.99 ± 3.15 vs. 3.97 ± 1.64%; p < 0.001. HP: 415 ± 86 vs. 134 ± 14 µg/g liver; p = 0.002) and decreased AST (555 ± 30 vs. 227 ± 83 IU/ml; p < 0.001) and ALT (538 ± 233 vs. 193 ± 86 IU/ml; p = 0.008). PX 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 or HR. Livers of CCl4-PX rats overexpressed FXR target genes including BSEP (2.5x), SHP (2.3x) and vasodilatory mediators CSH (2.1x) and DDAH (1.7x) while vasoconstrictive endothelin-1 (0.45), PDGF-Rβ (0.51x) and αSMA (0.61x) were reduced.

GS-9674 reduced fibrosis in NASH rats in a dose-dependent manner: SRA: VEH: 9.62 ± 4.60% vs. GS-9674 – 10 mg/kg: 5.64 ± 4.51% vs. GS-9674 – 30 mg/kg: 2.94 ± 1.28%; p < 0.001). HP content was reduced by GS-9674 – 10 mg/kg: 6.40 ± 1.33 mg/L and GS-9674 – 30 mg/kg: 6.98 ± 4.74 mg/L vs. NASH-VEH: 11.89 ± 2.90 mg/L (p = 0.030). GS-9674 – 30 mg/kg decreased hepatic col1a1 (-36.5%; p = 0.030) and pdgfr-b (-36.2%; p < 0.001) whereas shp expression was increased (+159%; p < 0.01). GS-9674 decreased PP (11.9 ± 2.1 vs. 8.9 ± 2.2 mmHg; p = 0.020), the combination of GS-9674+PROP reduced SMABF (14.18 ± 3.27 to 10.48 ± 3.74mL/min/100 g; p = 0.032) while not further decreasing PP.

Conclusions: PX20606 ameliorates liver fibrosis and portal pressure in toxic cirrhosis. The novel non-steroidal FXR agonist GS-9674 exerts dose-dependent antifibrotic effects and ameliorates portal hypertension in NASH rats. The combination of GS-9674 with propranolol results in an additional decrease of mesenteric hyperperfusion.