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 language | English (US) |
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Pages (from-to) | G1109-G1115 |
Journal | American Journal of Physiology - Gastrointestinal and Liver Physiology |
Volume | 272 |
Issue number | 5 35-5 |
DOIs | |
State | Published - May 1997 |
Keywords
- Baculovirus
- Cholestasis
- Deoxyribonucleic acid fragmentation
- Fast protein liquid chromatography
- Phospholipid vesicles
ASJC Scopus subject areas
- Physiology
- Hepatology
- Gastroenterology
- Physiology (medical)