Z Gastroenterol 2018; 56(05): e42
DOI: 10.1055/s-0038-1654645
POSTER
Hepatologie
Georg Thieme Verlag KG Stuttgart · New York

The FXR agonist GS-9674 reduces fibrosis and portal hypertension in a rat model of NASH

P Schwabl
1   Medical University of Vienna, Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Vienna, Austria
,
P Supper
1   Medical University of Vienna, Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Vienna, Austria
,
M Peck-Radosavljevic
2   Klinikum Klagenfurt/Innere Medizin und Gastroenterologie, Klagenfurt, Austria
,
M Trauner
1   Medical University of Vienna, Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Vienna, Austria
,
T Reiberger
1   Medical University of Vienna, Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Vienna, Austria
› Author Affiliations
Further Information

Publication History

Publication Date:
09 May 2018 (online)

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Background:

FXR agonists reduce fibrosis and portal pressure (PP) in rat models of toxic and cholestatic cirrhosis. Moreover, FXR agonists improve histological features of NASH in patients. We studied the effects of FXR agonism on hepatic fibrosis and hemodynamics in a rat model of advanced NASH with or without non-selective betablockade as standard treatment of portal hypertension.

Methods:

Male Wistar rats received a choline-deficient high-fat diet for 14 weeks with repeated NaNO2 injections (25 mg/kg i.p.,3x/week) to induce NASH. Vehicle or FXR agonist GS-9674 (30 mg/kg) were gavaged daily from weeks 4 – 14. In each group a subset received propranolol (25 mg/kg). Mean arterial pressure (MAP), heart rate (HR), portal pressure (PP) and superior mesenteric artery blood flow (SMABF) were measured. Fibrosis was assessed by Sirius Red area (SR) and collagen expression. As indicator of hepatic stellate cell (HSC) activation desmin area (DA) was quantified by immunofluorescence.

Results:

NASH rats had significant steatosis, fibrosis and portal hypertension compared to healthy controls. In GS-9674 treated NASH rats, liver fibrosis (SR: 10.5 ± 2.9 vs. 4.1 ± 2.0%; p = 0.001) and hepatic collagen expression (-43.7%; p = 0.032) were significantly reduced, compared to vehicle treated controls. In line, GS-9674 also significantly reduced HSC activation (DA: 5.9 ± 0.7 vs. 10.3 ± 0.8%; p = 0.004). Treatment with GS-9674 significantly decreased PP (8.9 ± 2.1 vs. 11.9 ± 2.0 mmHg; p = 0.020), without affecting systemic hemodynamics (MAP, HR). GS-9674 seemed to non-significantly increase SMABF by 10%. Interestingly, the combination of FXR agonism with propranolol significantly reduced SMABF (10.6 ± 3.9 vs. 14.8 ± 2.5 mL/min/100 g; p = 0.016) without further decreasing PP. However, in propranolol treated groups significant lower MAP and HR values were noted.

Conclusion:

The non-steroidal FXR agonist GS-9674 reduces liver fibrosis and HSC activation in NASH rats, and decreases portal pressure without deteriorating systemic hemodynamics. The combination of GS-9674 with propranolol additionally decreases mesenteric hyperperfusion, yet also affects mean arterial pressure and heart rate.