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

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 first time that PKC-dependent signaling pathways play a critical role in bile salt-induced hepatocyte apoptosis.

Bile acid feeding increased proliferative activity and apical bile acid transporter expression in both small and large rat cholangiocytes

“…BA have been shown to activate PKC in a variety of cells besides cholangiocytes. [16][17][18]46 PKC has been shown to modulate the gene expression of a number of proteins. [47][48][49][50] Our observation that BA regulate ABAT through the PKC system is novel because the mechanisms for the modulation of ABAT expression in the liver has not been previously elucidated.…”

Elevated L-PGDS activity contributes to PMA-induced apoptosis concomitant with downregulation of PI3-K

“…It is interesting to note that selenocompounds, which are known to inhibit L-PGDS enzymatic activity (6) and L-PGDS-induced apoptosis (13), have been shown to preferentially inhibit the calcium-dependent isoforms of PKC (4). In addition, bile salts, which are transported by L-PGDS in vivo, have been shown to activate PKC and induce apoptosis in hepatocytes (7). The possibility of other members of the MAPK family such as c-Jun NH 2 -terminal kinase and p38 MAPK participating in L-PGDS-mediated apoptosis needs to be examined so that we can more clearly define the role of the MAPK pathway in this process.…”

Phosphorylation of Bcl-2 plays an important role in glycochenodeoxycholate-induced survival and chemoresistance in HCC

“…Previous studies have shown that toxic bile salt glycochenodeoxycholate induces hepatocyte apoptosis involving ligand-independent oligomerization of Fas (3) and by promoting cytoplasmic transport of Fas to the cell surface (4). PKC-dependent signaling pathways play a critical role in bile salt-induced hepatocyte apoptosis (5,6). Endoplasmic reticulum is involved in glycochenodeoxycholic acid-induced apoptosis in rat hepatocytes, although its role may be smaller than mitochondria-mediated pathway (7).…”