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α 5 β 1 ‐integrins are sensors for tauroursodeoxycholic acid in hepatocytes
Author(s) -
Gohlke Holger,
Schmitz Birte,
Sommerfeld Annika,
Reinehr Roland,
Häussinger Dieter
Publication year - 2013
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.25992
Subject(s) - tauroursodeoxycholic acid , integrin , choleretic , medicine , hepatocyte , endocrinology , biology , signal transduction , biochemistry , receptor , in vitro , endoplasmic reticulum , unfolded protein response
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 α 5 β 1 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 β 1 subunit of α 5 β 1 integrins, followed by an activating phosphorylation of extracellular signal‐regulated kinases. TUDC‐induced kinase activation was no longer observed after β 1 integrin knockdown in isolated rat hepatocytes or in the presence of an integrin‐antagonistic hexapeptide in perfused rat liver. TUDC‐induced β 1 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 α 5 β 1 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 β 1 integrins, which trigger signal transduction pathways toward choleresis. (H EPATOLOGY 2013)