α5β1-integrins are sensors for tauroursodeoxycholic acid in hepatocytes

Authors

  • Holger Gohlke,

    1. Institute for Pharmaceutical and Medicinal Chemistry, Department of Mathematics and Natural Sciences, Heinrich-Heine-University Düsseldorf, Germany
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  • Birte Schmitz,

    1. Institute for Pharmaceutical and Medicinal Chemistry, Department of Mathematics and Natural Sciences, Heinrich-Heine-University Düsseldorf, Germany
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  • Annika Sommerfeld,

    1. Clinic for Gastroenterology, Hepatology and Infectious Diseases, Heinrich-Heine-University Düsseldorf, Germany
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  • Roland Reinehr,

    1. Clinic for Gastroenterology, Hepatology and Infectious Diseases, Heinrich-Heine-University Düsseldorf, Germany
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  • Dieter Häussinger

    Corresponding author
    1. Clinic for Gastroenterology, Hepatology and Infectious Diseases, Heinrich-Heine-University Düsseldorf, Germany
    • University Hospital Düsseldorf, Clinic for Gastroenterology, Hepatology and Infectious Diseases, Moorenstrasse 5, D-40225 Düsseldorf, Germany
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    • fax: +49 211 811 8838


  • Potential conflict of interest: Nothing to report.

Abstract

Ursodeoxycholic acid, which in vivo is converted to its taurine conjugate tauroursodeoxycholic acid (TUDC), is a mainstay for the treatment of cholestatic liver disease. Earlier work showed that TUDC exerts its choleretic properties in the perfused rat liver in an α5β1 integrin-mediated way. However, the molecular basis of TUDC-sensing in the liver is unknown. We herein show that TUDC (20 μmol/L) induces in perfused rat liver and human HepG2 cells the rapid appearance of the active conformation of the β1 subunit of α5β1 integrins, followed by an activating phosphorylation of extracellular signal-regulated kinases. TUDC-induced kinase activation was no longer observed after β1 integrin knockdown in isolated rat hepatocytes or in the presence of an integrin-antagonistic hexapeptide in perfused rat liver. TUDC-induced β1 integrin activation occurred predominantly inside the hepatocyte and required TUDC uptake by way of the Na+/taurocholate cotransporting peptide. Molecular dynamics simulations of a 3D model of α5β1 integrin with TUDC bound revealed significant conformational changes within the head region that have been linked to integrin activation before. Conclusions: TUDC can directly activate intrahepatocytic β1 integrins, which trigger signal transduction pathways toward choleresis. (HEPATOLOGY 2013)

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