Mitogen-activated protein kinases mediate the stimulation of bile acid secretion by tauroursodeoxycholate in rat liver

Gastroenterology. 1997 Oct;113(4):1306-14. doi: 10.1053/gast.1997.v113.pm9322526.

Abstract

Background & aims: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-Methyl-3-isobutylxanthine / pharmacology
  • Animals
  • Bucladesine / pharmacology
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
  • Cells, Cultured
  • Colforsin / pharmacology
  • Enzyme Activation
  • Enzyme Inhibitors / pharmacology
  • Flavonoids / pharmacology
  • GTP-Binding Proteins / metabolism
  • Indoles / pharmacology
  • Isomerism
  • Isoproterenol / pharmacology
  • Kinetics
  • Liver / drug effects
  • Liver / enzymology
  • Liver / physiology*
  • Male
  • Maleimides / pharmacology
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases*
  • Models, Biological
  • Protein Kinase C / antagonists & inhibitors
  • Protein Kinase C / metabolism
  • Protein-Tyrosine Kinases / antagonists & inhibitors
  • Rats
  • Rats, Wistar
  • Signal Transduction
  • Taurochenodeoxycholic Acid / pharmacology*
  • Taurocholic Acid / metabolism*
  • Tetradecanoylphorbol Acetate / pharmacology

Substances

  • Enzyme Inhibitors
  • Flavonoids
  • Indoles
  • Maleimides
  • Colforsin
  • Taurochenodeoxycholic Acid
  • Taurocholic Acid
  • ursodoxicoltaurine
  • Bucladesine
  • Protein-Tyrosine Kinases
  • Protein Kinase C
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases
  • GTP-Binding Proteins
  • Isoproterenol
  • bisindolylmaleimide I
  • Tetradecanoylphorbol Acetate
  • 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
  • 1-Methyl-3-isobutylxanthine