The human transcription factor AP-1 is a mediator of bile acid-induced liver cell apoptosis

Biochem Biophys Res Commun. 2006 Feb 17;340(3):800-6. doi: 10.1016/j.bbrc.2005.12.081. Epub 2005 Dec 20.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Chloromethyl Ketones / pharmacology
  • Apoptosis*
  • Bile Acids and Salts / metabolism*
  • Cell Line
  • Cell Line, Tumor
  • Cholestasis
  • Curcumin / pharmacology
  • Detergents / pharmacology
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / pharmacology
  • Genes, Reporter
  • Glycochenodeoxycholic Acid / pharmacology
  • Hepatocytes / metabolism
  • Humans
  • Immunoblotting
  • Liver / pathology*
  • Luciferases / metabolism
  • MAP Kinase Signaling System
  • Oligonucleotide Array Sequence Analysis
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction
  • Taurocholic Acid / metabolism
  • Time Factors
  • Transcription Factor AP-1 / metabolism
  • Transcription Factor AP-1 / physiology*
  • Transcription, Genetic
  • Up-Regulation
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Amino Acid Chloromethyl Ketones
  • Bile Acids and Salts
  • Detergents
  • Enzyme Inhibitors
  • Transcription Factor AP-1
  • benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone
  • Taurocholic Acid
  • Glycochenodeoxycholic Acid
  • Luciferases
  • p38 Mitogen-Activated Protein Kinases
  • Curcumin