Mitogen-activated protein kinases mediate the stimulation of bile acid secretion by tauroursodeoxycholate in rat liver.
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.
Schliess
F
F
Heinrich-Heine Universität, Klinik für Gastroenterologie, Hepatologie, und Infektiologie, Düsseldorf, Germany. freimut.schliess@uni-duesseldorf.de
Kurz
A K
AK
vom Dahl
S
S
Häussinger
D
D
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
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