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 −41% (10 mg/kg) and −69% (30 mg/kg), respectively. The 30 mg/kg
cilofexor dose significantly reduced hepatic hydroxyproline content (−41%), expression of col1a1
(−37%) and pdgfr-β (−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; p = 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