title: The FXR agonist PX20606 ameliorates portal hypertension by targeting vascular remodelling and sinusoidal dysfunction.
abstract: Steroidal farnesoid X receptor (FXR) agonists demonstrated potent anti-fibrotic activities and lowered portal hypertension in experimental models. The impact of the novel non-steroidal and selective FXR agonist PX20606 on portal hypertension and fibrosis was explored in this study.
  
  
  
  In experimental models of non-cirrhotic (partial portal vein ligation, PPVL, 7days) and cirrhotic (carbon tetrachloride, CCl4, 14weeks) portal hypertension, PX20606 (PX,10mg/kg) or the steroidal FXR agonist obeticholic acid (OCA,10mg/kg) were gavaged. We then measured portal pressure, intrahepatic vascular resistance, liver fibrosis and bacterial translocation.
  
  
  
  PX decreased portal pressure in non-cirrhotic PPVL (12.6±1.7 vs. 10.4±1.1mmHg; p=0.020) and cirrhotic CCl4(15.2±0.5 vs. 11.8±0.4mmHg; p=0.001) rats. In PPVL animals, we observed less bacterial translocation (-36%; p=0.041), a decrease in lipopolysaccharide binding protein (-30%; p=0.024) and splanchnic tumour necrosis factor α levels (-39%; p=0.044) after PX treatment. In CCl4rats, PX decreased fibrotic Sirius Red area (-43%; p=0.005), hepatic hydroxyproline (-66%; p<0.001), and expression of profibrogenic proteins (Col1a1, α smooth muscle actin, transforming growth factor β). CCl4-PX rats had significantly lower transaminase levels and reduced hepatic macrophage infiltration. Moreover, PX induced sinusoidal vasodilation (upregulation of cystathionase, dimethylaminohydrolase (DDAH)1, endothelial nitric oxide synthase (eNOS), GTP-cyclohydrolase1) and reduced intrahepatic vasoconstriction (downregulation of endothelin-1, p-Moesin). In cirrhosis, PX improved endothelial dysfunction (decreased von-Willebrand factor) and normalized overexpression of vascular endothelial growth factor, platelet-derived growth factor and angiopoietins. While short-term 3-day PX treatment reduced portal pressure (-14%; p=0.041) by restoring endothelial function, 14week PX therapy additionally inhibited sinusoidal remodelling and decreased portal pressure to a greater extent (-22%; p=0.001). In human liver sinusoidal endothelial cells, PX increased eNOS and DDAH expression.
  
  
  
  The non-steroidal FXR agonist PX20606 ameliorates portal hypertension by reducing liver fibrosis, vascular remodelling and sinusoidal dysfunction.
  
  
  
  The novel drug PX20606 activates the bile acid receptor FXR and shows beneficial effects in experimental liver cirrhosis: In the liver, it reduces scarring and inflammation, and also widens blood vessels. Thus, PX20606 leads to an improved blood flow through the liver and decreases hypertension of the portal vein. Additionally, PX20606 improves the altered intestinal barrier and decreases bacterial migration from the gut.
authors.affiliation: Div. of Gastroenterology and Hepatology, Dept. of Internal Medicine III, Medical University of Vienna, Vienna, Austria.
authors.forename: Philipp
authors.initials: P
authors.lastname: Schwabl
authors.affiliation: Phenex Pharmaceuticals, Waldhofer Strasse 104, 69123 Heidelberg, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Hambruch
authors.affiliation: Div. of Gastroenterology and Hepatology, Dept. of Internal Medicine III, Medical University of Vienna, Vienna, Austria.
authors.forename: Berit A
authors.initials: BA
authors.lastname: Seeland
authors.affiliation: Div. of Gastroenterology and Hepatology, Dept. of Internal Medicine III, Medical University of Vienna, Vienna, Austria.
authors.forename: Hubert
authors.initials: H
authors.lastname: Hayden
authors.affiliation: Div. of Gastroenterology and Hepatology, Dept. of Internal Medicine III, Medical University of Vienna, Vienna, Austria.
authors.forename: Michael
authors.initials: M
authors.lastname: Wagner
authors.affiliation: Div. of Gastroenterology and Hepatology, Dept. of Internal Medicine III, Medical University of Vienna, Vienna, Austria.
authors.forename: Lukas
authors.initials: L
authors.lastname: Garnys
authors.affiliation: Div. of Gastroenterology and Hepatology, Dept. of Internal Medicine III, Medical University of Vienna, Vienna, Austria.
authors.forename: Bastian
authors.initials: B
authors.lastname: Strobel
authors.affiliation: Div. of Gastroenterology and Hepatology, Dept. of Internal Medicine III, Medical University of Vienna, Vienna, Austria.
authors.forename: Tim-Lukas
authors.initials: TL
authors.lastname: Schubert
authors.affiliation: Div. of Gastroenterology and Hepatology, Dept. of Internal Medicine III, Medical University of Vienna, Vienna, Austria.
authors.forename: Florian
authors.initials: F
authors.lastname: Riedl
authors.affiliation: Vienna Medical Innovation Center (VMIC), Group Practice LABORS.at, Vienna, Austria.
authors.forename: Dieter
authors.initials: D
authors.lastname: Mitteregger
authors.affiliation: Synovo GmbH, Paul-Ehrlich-Str. 15, 72076 Tübingen, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Burnet
authors.affiliation: Dept. of Surgery, Medical University of Vienna, Vienna, Austria.
authors.forename: Patrick
authors.initials: P
authors.lastname: Starlinger
authors.affiliation: Dept. of Pathology, Medical University of Vienna, Vienna, Austria.
authors.forename: Georg
authors.initials: G
authors.lastname: Oberhuber
authors.affiliation: Phenex Pharmaceuticals, Waldhofer Strasse 104, 69123 Heidelberg, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Deuschle
authors.affiliation: Div. of Gastroenterology and Hepatology, Dept. of Internal Medicine III, Medical University of Vienna, Vienna, Austria.
authors.forename: Nataliya
authors.initials: N
authors.lastname: Rohr-Udilova
authors.affiliation: Dept. of Biomedical Research, Medical University of Vienna, Vienna, Austria.
authors.forename: Bruno K
authors.initials: BK
authors.lastname: Podesser
authors.affiliation: Div. of Gastroenterology and Hepatology, Dept. of Internal Medicine III, Medical University of Vienna, Vienna, Austria.
authors.forename: Markus
authors.initials: M
authors.lastname: Peck-Radosavljevic
authors.affiliation: Div. of Gastroenterology and Hepatology, Dept. of Internal Medicine III, Medical University of Vienna, Vienna, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Reiberger
authors.affiliation: Phenex Pharmaceuticals, Waldhofer Strasse 104, 69123 Heidelberg, Germany.
authors.forename: Claus
authors.initials: C
authors.lastname: Kremoser
authors.affiliation: Div. of Gastroenterology and Hepatology, Dept. of Internal Medicine III, Medical University of Vienna, Vienna, Austria. Electronic address: michael.trauner@meduniwien.ac.at.
authors.forename: Michael
authors.initials: M
authors.lastname: Trauner
mesh_terms: D000818:Animals; D001565:Benzoates / Q000627:therapeutic use*; D001647:Bile Acids and Salts / Q000096:biosynthesis; D001663:Bilirubin / Q000097:blood; D002196:Capillaries / Q000187:drug effects / Q000503:physiopathology; D002784:Cholesterol / Q000097:blood; D004195:Disease Models, Animal; D006975:Hypertension, Portal / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D007555:Isoxazoles / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists*; D066253:Vascular Remodeling / Q000187:drug effects* / Q000502:physiology; D014655:Vascular Resistance / Q000187:drug effects; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D001565:Benzoates; D001647:Bile Acids and Salts; D001663:Bilirubin; D002784:Cholesterol; D007555:Isoxazoles; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated; C000598200:4-(2-(2-chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)-4-isoxazolyl)methoxy)phenyl)cyclopropyl)benzoic acid
keywords: Bacterial translocation; Cirrhosis; FXR agonist; Farnesoid X receptor; Fibrosis; Intestinal permeability; Mouse; PX20606; Portal hypertension; Rat