The human transcription factor AP-1 is a mediator of bile acid-induced liver cell apoptosis.
Apoptosis induced by toxic bile acids is thought to contribute to liver injury during cholestasis. The transcription factor AP-1 is involved in the induction of apoptosis depending on stimulus and cell type. It is not known whether the major human toxic bile acid, glycochenodeoxycholic acid (GCDCA), modulates AP-1 in hepatocytes. Our data show that GCDCA (75 microM, 4 h) significantly upregulates cFos and JunB as demonstrated by microarray analysis and real-time PCR in HepG2-Ntcp hepatoma cells. GCDCA (75 microM, 4 h) also induced AP-1 activation as determined by EMSA that was most distinct after 30 min. In parallel, AP-1 transcriptional activity increased by 40% after exposure to GCDCA. Curcumin, an AP-1 inhibitor, dose-dependently reduced (1-25 microM) or completely abolished (50 microM) the apoptotic effect of GCDCA. Thus, GCDCA-induced upregulation of AP-1-dependent genes appears important for the cytotoxicity of this bile acid.
Bernt
Carina
C
Department of Medicine II-Grosshadern, University of Munich, Munich, Germany.
Vennegeerts
Timo
T
Beuers
Ulrich
U
Rust
Christian
C
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D017209:Apoptosis; D001647:Bile Acids and Salts / Q000378:metabolism*; D002460:Cell Line; D045744:Cell Line, Tumor; D002779:Cholestasis; D003474:Curcumin / Q000494:pharmacology; D003902:Detergents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D017930:Genes, Reporter; D005999:Glycochenodeoxycholic Acid / Q000494:pharmacology; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D008099:Liver / Q000473:pathology*; D008156:Luciferases / Q000378:metabolism; D020935:MAP Kinase Signaling System; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013656:Taurocholic Acid / Q000378:metabolism; D013997:Time Factors; D018808:Transcription Factor AP-1 / Q000378:metabolism / Q000502:physiology*; D014158:Transcription, Genetic; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D000590:Amino Acid Chloromethyl Ketones; D001647:Bile Acids and Salts; D003902:Detergents; D004791:Enzyme Inhibitors; D018808:Transcription Factor AP-1; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D013656:Taurocholic Acid; D005999:Glycochenodeoxycholic Acid; D008156:Luciferases; D048051:p38 Mitogen-Activated Protein Kinases; D003474:Curcumin