Tauroursodeoxycholic acid reduces bile acid-induced apoptosis by modulation of AP-1.
Ursodeoxycholic acid (UDCA) is used in the therapy of cholestatic liver diseases. Apoptosis induced by toxic bile acids plays an important role in the pathogenesis of liver injury during cholestasis and appears to be mediated by the human transcription factor AP-1. We aimed to study if TUDCA can decrease taurolitholic acid (TLCA)-induced apoptosis by modulating AP-1. TLCA (20 microM) upregulated AP-1 proteins cFos (26-fold) and JunB (11-fold) as determined by quantitative real-time PCR in HepG2-Ntcp hepatoma cells. AP-1 transcriptional activity increased by 300% after exposure to TLCA. cFos and JunB expression as well as AP-1 transcriptional activity were unaffected by TUDCA (75 microM). However, TUDCA significantly decreased TLCA-induced upregulation of cFos and JunB. Furthermore, TUDCA inhibited TLCA-induced AP-1 transcriptional activity and reduced TLCA-induced apoptosis. These data suggest that reversal of bile acid-induced AP-1 activation may be relevant for the antiapoptotic effect of TUDCA in liver cells.
Pusl
Thomas
T
Department of Medicine II - Grosshadern, University of Munich, Marchioninistrasse 15, 81377 Munich, Germany.
Vennegeerts
Timo
T
Wimmer
Ralf
R
Denk
Gerald U
GU
Beuers
Ulrich
U
Rust
Christian
C
D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001483:Base Sequence; D001647:Bile Acids and Salts; D002478:Cells, Cultured; D002756:Cholagogues and Choleretics / Q000494:pharmacology / Q000627:therapeutic use*; D002779:Cholestasis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008107:Liver Diseases / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D013655:Taurochenodeoxycholic Acid / Q000494:pharmacology / Q000627:therapeutic use*; D013658:Taurolithocholic Acid / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism*
D001647:Bile Acids and Salts; D002756:Cholagogues and Choleretics; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1; D013655:Taurochenodeoxycholic Acid; D013658:Taurolithocholic Acid; C031655:ursodoxicoltaurine