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Role of mitogen-activated protein kinases in tauroursodeoxycholic acid-induced bile formation in cholestatic rat liver

Authors

  • Gerald Ulrich Denk,

    1. Department of Medicine II-Grosshadern, Klinikum of the University of Munich, Munich, Germany, and
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  • Simon Hohenester,

    1. Department of Medicine II-Grosshadern, Klinikum of the University of Munich, Munich, Germany, and
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  • Ralf Wimmer,

    1. Department of Medicine II-Grosshadern, Klinikum of the University of Munich, Munich, Germany, and
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  • Claudia Böhland,

    1. Department of Medicine II-Grosshadern, Klinikum of the University of Munich, Munich, Germany, and
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  • Christian Rust,

    1. Department of Medicine II-Grosshadern, Klinikum of the University of Munich, Munich, Germany, and
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  • Ulrich Beuers

    Corresponding author
    1. Department of Gastroenterology and Hepatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
      Dr Ulrich Beuers, Department of Gastroenterology and Hepatology, G4-213, Academic Medical Center, University of Amsterdam, PO Box 22700, NL-1100 DE Amsterdam, The Netherlands. Email: u.h.beuers@amc.uva.nl
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Dr Ulrich Beuers, Department of Gastroenterology and Hepatology, G4-213, Academic Medical Center, University of Amsterdam, PO Box 22700, NL-1100 DE Amsterdam, The Netherlands. Email: u.h.beuers@amc.uva.nl

Abstract

Aim:  Ursodeoxycholic acid exerts anticholestatic effects in various cholestatic disorders and experimental models of cholestasis. Its taurine conjugate (TUDCA) stimulates bile salt secretion in isolated perfused rat livers (IPRL) under physiological, non-cholestatic conditions, in part by mitogen-activated protein kinase (MAPK)-dependent mechanisms. The role of MAPK in the anticholestatic effect of TUDCA, however, is unclear. Therefore, we studied the role of MAPK in the anticholestatic effect of TUDCA in IPRL and isolated rat hepatocytes (IRH) in taurolithocholic acid (TLCA)-induced cholestasis.

Methods:  Bile flow, biliary levels of 2,4-dinitrophenyl-S-glutathione (GS-DNP) as a marker of hepatobiliary organic anion secretion and activity of lactate dehydrogenase (LDH) in hepatovenous effluate as a marker of hepatocellular damage in IPRL perfused with TUDCA and/or TLCA were determined in the presence or absence of MAPK inhibitors. In addition, phosphorylation of Erk 1/2 and p38MAPK induced by TUDCA and/or TLCA was studied by Western immunoblot in IPRL and IRH.

Results:  TUDCA-induced bile flow was impaired by the Erk 1/2 inhibitor PD98059 in normal livers (−28%), but not in livers made cholestatic by TLCA. GS-DNP secretion was unaffected by PD98059 under both conditions. TUDCA-induced bile formation and organic anion secretion both in the presence and absence of TLCA were unaffected by the p38MAPK inhibitor SB202190. Erk 1/2 phosphorylation in liver tissue was unchanged after bile salt exposure for 70 min, but was transiently enhanced by TUDCA in IRH.

Conclusion:  MAPK do not mediate the anticholestatic effects of TUDCA in TLCA-induced cholestasis.

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