alpha(5)beta(1)-integrins are sensors for tauroursodeoxycholic acid in hepatocytes

作者：Gohlke Holger; Schmitz Birte; Sommerfeld Annika; Reinehr Roland; Haeussinger Dieter

来源：Hepatology, 2013, 57(3): 1117-1129.

DOI：10.1002/hep.25992

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 51 integrin-mediated way. However, the molecular basis of TUDC-sensing in the liver is unknown. We herein show that TUDC (20 mol/L) induces in perfused rat liver and human HepG2 cells the rapid appearance of the active conformation of the 1 subunit of 51 integrins, followed by an activating phosphorylation of extracellular signal-regulated kinases. TUDC-induced kinase activation was no longer observed after 1 integrin knockdown in isolated rat hepatocytes or in the presence of an integrin-antagonistic hexapeptide in perfused rat liver. TUDC-induced 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 51 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 1 integrins, which trigger signal transduction pathways toward choleresis. (HEPATOLOGY 2013)

• 出版日期2013-3