Bile salt-induced apoptosis of hepatocytes involves activation of protein kinase C
| Autor: | R. T. Stravitz, Y. P. Rao, Blake Jones, G. J. Gores |
|---|---|
| Rok vydání: | 1997 |
| Předmět: |
Programmed cell death
Physiology Apoptosis Biology Bile Acids and Salts chemistry.chemical_compound Glycochenodeoxycholic Acid Cholestasis Physiology (medical) Endopeptidases Phosphoprotein Phosphatases medicine Animals Enzyme Inhibitors Cells Cultured Protein Kinase C Protein kinase C Hepatology Gastroenterology Biological Transport medicine.disease Rats Cell biology Enzyme Activation Isoenzymes Chelerythrine medicine.anatomical_structure Liver Biochemistry chemistry Hepatocyte Phorbol Signal transduction |
| Zdroj: | American Journal of Physiology-Gastrointestinal and Liver Physiology. 272:G1109-G1115 |
| ISSN: | 1522-1547 0193-1857 |
| Popis: | 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-alpha, PKC-delta, and PKC-epsilon to hepatocyte membranes after administration of GCDC. Direct activation of PKC-alpha and PKC-delta 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. |
| Databáze: | OpenAIRE |
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