title: Mitogen-activated protein kinases mediate the stimulation of bile acid secretion by tauroursodeoxycholate in rat liver.
abstract: OBJECTIVE
  Tauroursodeoxycholate (TUDCA) is widely used in the treatment of cholestatic liver disease. The purpose of this study was to elucidate molecular mechanisms underlying its beneficial effect.
  
  
  METHODS
  TUDCA-induced signaling towards bile acid excretion was studied in 24-hour-cultured rat hepatocytes and perfused rat liver.
  
  
  RESULTS
  In rat hepatocytes, TUDCA (> 100 mumol/L) led within 10 minutes to an activation of the mitogen-activated protein (MAP)-kinases extracellular signal-regulated kinase (Erk)-1 and Erk-2. Erk activation by TUDCA was insensitive to inhibition of protein kinase C, tyrosine kinases, and G-protein function. TUDCA-induced Erk activation, however, was abolished in the presence of PD098059, a MAP-kinase kinase (MAP-kinase/Erk-kinase [MEK]) inhibitor and after elevation of intracellular adenosine 3',5'-cyclic monophosphate. Thus, TUDCA signaling towards MAP kinases is different from hypo-osmotic MAP-kinase activation, which is sensitive to inhibitors of tyrosine kinases and G-protein function. Addition of dibutyryl-adenosine 3',5'-cyclic monophosphate or PD098059 also abolished the stimulatory effect of TUDCA (20 mumol/L) on taurocholate excretion in perfused rat liver, whereas tyrosine kinase inhibition was ineffective.
  
  
  CONCLUSIONS
  TUDCA signaling towards bile acid secretion is mediated by an Raf/MEK-dependent activation of MAP kinases. Although both TUDCA and hypo-osmotic hepatocyte swelling lead to MAP-kinase activation and a stimulation of bile acid secretion, different upstream signaling events are involved.
authors.affiliation: Heinrich-Heine Universität, Klinik für Gastroenterologie, Hepatologie, und Infektiologie, Düsseldorf, Germany. freimut.schliess@uni-duesseldorf.de
authors.forename: F
authors.initials: F
authors.lastname: Schliess
authors.forename: A K
authors.initials: AK
authors.lastname: Kurz
authors.forename: S
authors.initials: S
authors.lastname: vom Dahl
authors.forename: D
authors.initials: D
authors.lastname: Häussinger
mesh_terms: D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000818:Animals; D003994:Bucladesine / Q000494:pharmacology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology; D007536:Isomerism; D007545:Isoproterenol / Q000494:pharmacology; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D008297:Male; D008301:Maleimides / Q000494:pharmacology; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D008954:Models, Biological; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D013655:Taurochenodeoxycholic Acid / Q000494:pharmacology*; D013656:Taurocholic Acid / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D005419:Flavonoids; D007211:Indoles; D008301:Maleimides; D005576:Colforsin; D013655:Taurochenodeoxycholic Acid; D013656:Taurocholic Acid; C031655:ursodoxicoltaurine; D003994:Bucladesine; D011505:Protein-Tyrosine Kinases; D011493:Protein Kinase C; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D019204:GTP-Binding Proteins; D007545:Isoproterenol; C070515:bisindolylmaleimide I; D013755:Tetradecanoylphorbol Acetate; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D015056:1-Methyl-3-isobutylxanthine