Bile salts mediate hepatocyte apoptosis by increasing cell surface trafficking of Fas

Thomas Sodeman, Steven F. Bronk, Patricia J. Roberts, Hideyuki Miyoshi, Gregory J. Gores

Research output: Contribution to journalArticle

186 Scopus citations

Abstract

Toxic bile salts induce hepatocyte apoptosis by a Fas-dependent, Fas ligand-independent mechanism. To account for this observation, we formulated the hypothesis that toxic bile salts induce apoptosis by effecting translocation of cytoplasmic Fas to the cell surface, resulting in transduction of Fas death signals. In McNtcp.24 cells the majority of Fas was cytoplasmic, as assessed by cell fractionation and immunofluorescence studies. However, cell surface Fas increased sixfold after treatment with the toxic bile salt glycochenodeoxycholate (GCDC) in the absence of increased Fas protein expression. Moreover, in cells transfected with Fas-green fluorescence protein, cell surface fluorescence also increased in GCDC- treated cells, directly demonstrating Fas translocation to the plasma membrane. Both brefeldin A, a Golgi-disrupting agent, and nocodazole, a microtubule inhibitor, prevented the GCDC-induced increase in cell surface Fas and apoptosis. In conclusion, toxic bile salts appear to induce apoptosis by promoting cytoplasmic transport of Fas to the cell surface by a Golgi- and microtubule-dependent pathway.

Original languageEnglish (US)
Pages (from-to)G992-G999
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume278
Issue number6 41-6
DOIs
StatePublished - Jun 2000

Keywords

  • Brefeldin A
  • Fas-green fluorescence protein
  • JO-2 antisera
  • Nocodazole
  • Vesicle trafficking

ASJC Scopus subject areas

  • Physiology
  • Hepatology
  • Gastroenterology
  • Physiology (medical)

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