Bile salt-induced apoptosis of hepatocytes involves activation of protein kinase C

Blake A. Jones, Yi Ping Rao, R. Todd Stravitz, Gregory J. Gores

Research output: Contribution to journalArticle

120 Scopus citations

Abstract

Toxic bile salts induce hepatocyte apoptosis, a model relevant to liver injury during cholestasis. However, the signaling mechanisms culminating in bile salt-induced apoptosis remain unclear. Because protein kinase C (PKC) is activated by bile salts in hepatocytes and causes apoptosis in other cells, we tested the hypothesis that bile salt-induced hepatocyte apoptosis is mediated by PKC. The PKC inhibitors chelerythrine and Go-6976 reduced, whereas a PKC agonist, phorbol 12-myristate 13-acetate (PMA), increased glycochenodeoxycholate (GCDC)-induced hepatocyte apoptosis. Membrane- associated total PKC activity was increased in GCDC-treated hepatocytes. Quantitative immunoblot analysis demonstrated membrane translocation of PKC- α, PKC-σ, and PKC-ε to hepatocyte membranes after administration of GCDC. Direct activation of PKC-α and PKC-σ by GCDC was also demonstrated using recombinant, baculovirus-expressed PKC isoforms in a medium of defined lipid composition. Chelerythrine and Go-6976 reduced, whereas PMA enhanced, cathepsin B activity during treatment of hepatocytes with GCDC, demonstrating coupling of PKC activity to the protease effector mechanisms of apoptosis. In conclusion, our data suggest for the first time that PKC-dependent signaling pathways play a critical role in bile salt-induced hepatocyte apoptosis.

Original languageEnglish (US)
Pages (from-to)G1109-G1115
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume272
Issue number5 35-5
DOIs
StatePublished - May 1997

Keywords

  • Baculovirus
  • Cholestasis
  • Deoxyribonucleic acid fragmentation
  • Fast protein liquid chromatography
  • Phospholipid vesicles

ASJC Scopus subject areas

  • Physiology
  • Hepatology
  • Gastroenterology
  • Physiology (medical)

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