AJP - Gastrointestinal and Liver Physiology, Vol 272, Issue 5 1109-G1115, Copyright © 1997 by American Physiological Society

ARTICLES

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

B. A. Jones, Y. P. Rao, R. T. Stravitz and G. J. Gores
Center for Basic Research in Digestive Diseases, Mayo Clinic, Rochester, Minnesota, USA.

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.

This article has been cited by other articles:

				G. Alpini, N. Kanno, J. L. Phinizy, S. Glaser, H. Francis, S. Taffetani, and G. LeSage Tauroursodeoxycholate inhibits human cholangiocarcinoma growth via Ca2+-, PKC-, and MAPK-dependent pathways Am J Physiol Gastrointest Liver Physiol, June 1, 2004; 286(6): G973 - G982. [Abstract] [Full Text] [PDF]

				M. J. Redlak, M. S. Dennis, and T. A. Miller Apoptosis is a major mechanism of deoxycholate-induced gastric mucosal cell death Am J Physiol Gastrointest Liver Physiol, November 1, 2003; 285(5): G870 - G879. [Abstract] [Full Text] [PDF]

				H. Higuchi and G. J. Gores Bile Acid Regulation of Hepatic Physiology: IV. Bile acids and death receptors Am J Physiol Gastrointest Liver Physiol, May 1, 2003; 284(5): G734 - G738. [Abstract] [Full Text] [PDF]

				S. Glaser, D. Alvaro, T. Roskams, J. L. Phinizy, G. Stoica, H. Francis, Y. Ueno, B. Barbaro, M. Marzioni, J. Mauldin, et al. Dopaminergic inhibition of secretin-stimulated choleresis by increased PKC-gamma expression and decrease of PKA activity Am J Physiol Gastrointest Liver Physiol, April 1, 2003; 284(4): G683 - G694. [Abstract] [Full Text] [PDF]

				L. Ragolia, T. Palaia, E. Paric, and J. K. Maesaka Elevated L-PGDS activity contributes to PMA-induced apoptosis concomitant with downregulation of PI3-K Am J Physiol Cell Physiol, January 1, 2003; 284(1): C119 - C126. [Abstract] [Full Text] [PDF]

				H. Higuchi, H. Miyoshi, S. F. Bronk, H. Zhang, N. Dean, and G. J. Gores Bid Antisense Attenuates Bile Acid-Induced Apoptosis and Cholestatic Liver Injury J. Pharmacol. Exp. Ther., December 1, 2001; 299(3): 866 - 873. [Abstract] [Full Text] [PDF]

				L. Qiao, E. Studer, K. Leach, R. McKinstry, S. Gupta, R. Decker, R. Kukreja, K. Valerie, P. Nagarkatti, W. E. Deiry, et al. Deoxycholic Acid (DCA) Causes Ligand-independent Activation of Epidermal Growth Factor Receptor (EGFR) and FAS Receptor in Primary Hepatocytes: Inhibition of EGFR/Mitogen-activated Protein Kinase-Signaling Module Enhances DCA-induced Apoptosis Mol. Biol. Cell, September 1, 2001; 12(9): 2629 - 2645. [Abstract] [Full Text] [PDF]

				Q. Chang and B. L. Tepperman The role of protein kinase C isozymes in TNF-{alpha}-induced cytotoxicity to a rat intestinal epithelial cell line Am J Physiol Gastrointest Liver Physiol, April 1, 2001; 280(4): G572 - G583. [Abstract] [Full Text] [PDF]

				B. L. Tepperman, Q. Chang, and B. D. Soper Protein Kinase C Mediates Lipopolysaccharide- and Phorbol-Induced Nitric-Oxide Synthase Activity and Cellular Injury in the Rat Colon J. Pharmacol. Exp. Ther., December 1, 2000; 295(3): 1249 - 1257. [Abstract] [Full Text]

				K. Schlottmann, F.-P. Wachs, R. Christian Krieg, F. Kullmann, J. Schölmerich, and G. Rogler Characterization of Bile Salt-induced Apoptosis in Colon Cancer Cell Lines Cancer Res., August 1, 2000; 60(15): 4270 - 4276. [Abstract] [Full Text]

				T. Sodeman, S. F. Bronk, P. J. Roberts, H. Miyoshi, and G. J. Gores Bile salts mediate hepatocyte apoptosis by increasing cell surface trafficking of Fas Am J Physiol Gastrointest Liver Physiol, June 1, 2000; 278(6): G992 - G999. [Abstract] [Full Text] [PDF]

				J. F. Brown, Q. Chang, B. D. Soper, and B. L. Tepperman Protein kinase C mediates experimental colitis in the rat Am J Physiol Gastrointest Liver Physiol, March 1, 1999; 276(3): G583 - G590. [Abstract] [Full Text] [PDF]

				G. C. Mayne and A. W. Murray Evidence That Protein Kinase Cepsilon Mediates Phorbol Ester Inhibition of Calphostin C- and Tumor Necrosis Factor-alpha -induced Apoptosis in U937 Histiocytic Lymphoma Cells J. Biol. Chem., September 11, 1998; 273(37): 24115 - 24121. [Abstract] [Full Text] [PDF]

				B. A. Jones and G. J. Gores Physiology and pathophysiology of apoptosis in epithelial cells of the liver, pancreas, and intestine Am J Physiol Gastrointest Liver Physiol, December 1, 1997; 273(6): G1174 - G1188. [Abstract] [Full Text] [PDF]

				H. H. Nietsch, M. W. Roe, J. F. Fiekers, A. L. Moore, and S. D. Lidofsky Activation of Potassium and Chloride Channels by Tumor Necrosis Factor alpha . ROLE IN LIVER CELL DEATH J. Biol. Chem., June 30, 2000; 275(27): 20556 - 20561. [Abstract] [Full Text] [PDF]

				R. Wang, M. Salem, I. M. Yousef, B. Tuchweber, P. Lam, S. J. Childs, C. D. Helgason, C. Ackerley, M. J. Phillips, and V. Ling Targeted inactivation of sister of P-glycoprotein gene (spgp) in mice results in nonprogressive but persistent intrahepatic cholestasis PNAS, February 13, 2001; 98(4): 2011 - 2016. [Abstract] [Full Text] [PDF]