title: Tauroursodeoxycholate Protects Rat Hepatocytes from Bile Acid-Induced Apoptosis via β1-Integrin- and Protein Kinase A-Dependent Mechanisms.
abstract: OBJECTIVE
  Ursodeoxycholic acid, which in vivo is rapidly converted into its taurine conjugate, is frequently used for the treatment of cholestatic liver disease. Apart from its choleretic effects, tauroursodeoxycholate (TUDC) can protect hepatocytes from bile acid-induced apoptosis, but the mechanisms underlying its anti-apoptotic effects are poorly understood.
  
  
  METHODS
  These mechanisms were investigated in perfused rat liver and isolated rat hepatocytes.
  
  
  RESULTS
  It was found that TUDC inhibited the glycochenodeoxycholate (GCDC)-induced activation of the CD95 death receptor at the level of association between CD95 and the epidermal growth factor receptor. This was due to a rapid TUDC-induced β1-integrin-dependent cyclic AMP (cAMP) signal with induction of the dual specificity mitogen-activated protein (MAP) kinase phosphatase 1 (MKP-1), which prevented GCDC-induced phosphorylation of mitogen-activated protein kinase kinase 4 (MKK4) and c-jun-NH2-terminal kinase (JNK) activation. Furthermore, TUDC induced a protein kinase A (PKA)-mediated serine/threonine phosphorylation of the CD95, which was recently identified as an internalization signal for CD95. Furthermore, TUDC inhibited GCDC-induced CD95 targeting to the plasma membrane in a β1-integrin-and PKA-dependent manner. In line with this, the β1-integrin siRNA knockdown in sodium taurocholate cotransporting polypeptide (Ntcp)-transfected HepG2 cells abolished the protective effect of TUDC against GCDC-induced apoptosis.
  
  
  CONCLUSIONS
  TUDC exerts its anti-apoptotic effect via a β1-integrin-mediated formation of cAMP, which prevents CD95 activation by hydrophobic bile acids at the levels of JNK activation and CD95 serine/threonine phosphorylation.
authors.affiliation: Clinic for Gastroenterology, Hepatology and Infectious Diseases, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.
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: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics* / Q000378:metabolism; D054638:Dual Specificity Phosphatase 1 / Q000235:genetics / Q000378:metabolism; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D005999:Glycochenodeoxycholic Acid / Q000037:antagonists & inhibitors* / Q000633:toxicity; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D019012:Integrin beta1 / Q000235:genetics* / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000378:metabolism; D008297:Male; D009924:Organ Culture Techniques; D029363:Organic Anion Transporters, Sodium-Dependent / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D061251:Primary Cell Culture; D011673:Pulsatile Flow; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D027981:Symporters / Q000235:genetics / Q000378:metabolism; D013655:Taurochenodeoxycholic Acid / Q000494:pharmacology*; D019014:fas Receptor / Q000235:genetics / Q000378:metabolism
chemical_list: D019012:Integrin beta1; D029363:Organic Anion Transporters, Sodium-Dependent; D027981:Symporters; D019014:fas Receptor; C071908:sodium-bile acid cotransporter; D013655:Taurochenodeoxycholic Acid; C031655:ursodoxicoltaurine; D005999:Glycochenodeoxycholic Acid; D000242:Cyclic AMP; D066246:ErbB Receptors; D017868:Cyclic AMP-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D054638:Dual Specificity Phosphatase 1; C517021:Dusp1 protein, rat