title: Obeticholic acid, a farnesoid X receptor agonist, improves portal hypertension by two distinct pathways in cirrhotic rats.
abstract: The farnesoid X receptor (FXR) is a nuclear bile acid receptor involved in bile acid homeostasis, hepatic and intestinal inflammation, liver fibrosis, and cardiovascular disease. We studied the effect of short-term treatment with obeticholic acid (INT-747), a potent selective FXR agonist, on intrahepatic hemodynamic dysfunction and signaling pathways in different rat models of cirrhotic portal hypertension (PHT). For this, thioacetamide (TAA)-intoxicated and bile-duct-ligated (BDL) rats were used as models. After gavage of two doses of 30 mg/kg of INT-747 or vehicle within 24 hours, in vivo hemodynamics were assessed. Additionally, we evaluated the direct effect of INT-747 on total intrahepatic vascular resistance (IHVR) and intrahepatic vascular tone (endothelial dysfunction and hyperresponsiveness to methoxamine) by means of an in situ liver perfusion system and on hepatic stellate cell contraction in vitro. FXR expression and involved intrahepatic vasoactive pathways (e.g., endothelial nitric oxide synthase [eNOS], Rho-kinase, and dimethylarginine dimethylaminohydrolase [DDAH]) were analyzed by immunohistochemistry, reverse-transcriptase polymerase chain reaction, or western blotting. In both cirrhotic models, FXR expression was decreased. Treatment with INT-747 in TAA and BDL reactivated the FXR downstream signaling pathway and decreased portal pressure by lowering total IHVR without deleterious systemic hypotension. In the perfused TAA and BDL cirrhotic liver, INT-747 improved endothelial vasorelaxation capacity, but not hyperresponsiveness. In both groups, this was associated with an increased eNOS activity, which, in TAA, related to down-regulation of Rho-kinase and in BDL to up-regulation of DDAH-2.
  
  
  CONCLUSIONS
  FXR agonist INT-747 improves PHT in two different rat models of cirrhosis by decreasing IHVR. This hemodynamic effect relates to increased intrahepatic eNOS activity by pathways that differ depending on the etiology of cirrhosis.
authors.affiliation: Department of Liver and Biliopancreatic Disorders, University Hospital Gasthuisberg, University of Leuven, Leuven, Belgium.
authors.forename: Len
authors.initials: L
authors.lastname: Verbeke
authors.forename: Ricard
authors.initials: R
authors.lastname: Farre
authors.forename: Jonel
authors.initials: J
authors.lastname: Trebicka
authors.forename: Mina
authors.initials: M
authors.lastname: Komuta
authors.forename: Tania
authors.initials: T
authors.lastname: Roskams
authors.forename: Sabine
authors.initials: S
authors.lastname: Klein
authors.forename: Ingrid Vander
authors.initials: IV
authors.lastname: Elst
authors.forename: Petra
authors.initials: P
authors.lastname: Windmolders
authors.forename: Tim
authors.initials: T
authors.lastname: Vanuytsel
authors.forename: Frederik
authors.initials: F
authors.lastname: Nevens
authors.forename: Wim
authors.initials: W
authors.lastname: Laleman
mesh_terms: D000818:Animals; D002635:Chenodeoxycholic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D015536:Down-Regulation; D004353:Drug Evaluation, Preclinical; D006975:Hypertension, Portal / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000150:complications / Q000503:physiopathology; D008297:Male; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists; D015398:Signal Transduction / Q000502:physiology*; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D002635:Chenodeoxycholic Acid; D052250:Nitric Oxide Synthase Type III; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated; C464660:obeticholic acid; C496316:Nos3 protein, rat