title: α5 β1-integrins are sensors for tauroursodeoxycholic acid in hepatocytes.
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 α5 β1 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 α5 β1 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 α5 β1 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).
authors.affiliation: Institute for Pharmaceutical and Medicinal Chemistry, Department of Mathematics and Natural Sciences, Heinrich-Heine-University Düsseldorf, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Gohlke
authors.forename: Birte
authors.initials: B
authors.lastname: Schmitz
authors.forename: Annika
authors.initials: A
authors.lastname: Sommerfeld
authors.forename: Roland
authors.initials: R
authors.lastname: Reinehr
authors.forename: Dieter
authors.initials: D
authors.lastname: Häussinger
mesh_terms: D000494:Allosteric Regulation / Q000502:physiology; D000818:Animals; D019281:Dimerization; D049452:Green Fluorescent Proteins / Q000235:genetics; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D039081:Integrin alpha5beta1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008297:Male; D009842:Oligopeptides / Q000378:metabolism / Q000494:pharmacology; D029363:Organic Anion Transporters, Sodium-Dependent / Q000235:genetics / Q000378:metabolism; D017433:Protein Structure, Secondary / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000502:physiology; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D027981:Symporters / Q000235:genetics / Q000378:metabolism; D013655:Taurochenodeoxycholic Acid / Q000378:metabolism* / Q000494:pharmacology; D013656:Taurocholic Acid / Q000378:metabolism / Q000494:pharmacology; D014580:Ursodeoxycholic Acid / Q000493:pharmacokinetics
chemical_list: D039081:Integrin alpha5beta1; D009842:Oligopeptides; D029363:Organic Anion Transporters, Sodium-Dependent; D034741:RNA, Small Interfering; D027981:Symporters; C485184:enhanced green fluorescent protein; C071908:sodium-bile acid cotransporter; D049452:Green Fluorescent Proteins; D013655:Taurochenodeoxycholic Acid; D013656:Taurocholic Acid; C031655:ursodoxicoltaurine; D014580:Ursodeoxycholic Acid; C058161:glycyl-arginyl-glycyl-aspartyl-seryl-proline