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

The American Journal of Physiology
B JonesG J Gores

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 Gö-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 Gö-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 fir...Continue Reading

Citations

Jun 22, 2000·American Journal of Physiology. Gastrointestinal and Liver Physiology·T SodemanG J Gores
Jun 7, 2003·American Journal of Physiology. Gastrointestinal and Liver Physiology·Maria J RedlakThomas A Miller
Nov 16, 2006·World Journal of Gastroenterology : WJG·Patrick-L SplinterNicholas-F LaRusso
Nov 2, 2014·American Journal of Physiology. Gastrointestinal and Liver Physiology·Cynthia R L WebsterM Sawkat Anwer
Apr 25, 2019·International Journal of Molecular Sciences·Leonardo BaiocchiGianfranco Alpini
Jul 18, 2009·World Journal of Gastroenterology : WJG·Harris BernsteinKaterina Dvorak
Dec 31, 2002·American Journal of Physiology. Gastrointestinal and Liver Physiology·Shannon GlaserGianfranco Alpini
Jan 1, 2004·American Journal of Physiology. Gastrointestinal and Liver Physiology·Gianfranco AlpiniGene LeSage
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Apr 10, 2003·American Journal of Physiology. Gastrointestinal and Liver Physiology·Hajime Higuchi, Gregory J Gores

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Apoptosis

Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis