Cytoprotective effect of tauroursodeoxycholate on hepatocyte apoptosis induced by peroxisome proliferator-activated receptor gamma ligand.
OBJECTIVE
Peroxisome proliferator-activated receptor gamma (PPARgamma) ligands inhibit cell growth and induce apoptosis in various cancer cells. Bile acids are also known to cause hepatocyte apoptosis through nuclear receptor-mediated mechanisms. The aim of this study was to examine the effect of two different bile acid species on the inhibitory action of PPARgamma in cell growth with paying attention to the role of the mitogen-activated protein kinase pathway as an underlying mechanism.


METHODS
Immortalized human hepatocytes (OUMS-29) and hepatoma cells (HepG2 and Huh7) were incubated with troglitazone (TGZ), a PPARgamma ligand with or without pre-incubation of either hydrophobic glycochenodeoxycholate (GCDC) or hydrophilic tauroursodeoxycholate (TUDC).


RESULTS
TGZ induced cell apoptosis in all cell types, resulting in the reduction of cell viability. While pre-incubation with GCDC enhanced the apoptotic effects of TGZ, TUDC significantly attenuated it. Both bile acids enhanced p38 and c-Jun N-terminal kinase (JNK) phosphorylation in a similar way, whereas there was more drastic enhancement of extracellular signal-regulated kinase (ERK) 1/2 phosphorylation in the presence of TUDC compared to GCDC. In addition, ERK inhibitors suppressed the action of TUDC against apoptotic effect of TGZ.


CONCLUSIONS
This study demonstrates that TUDC exhibits anti-apoptotic and cytoprotective effects against TGZ-induced cell apoptosis, presumably through the ERK signaling pathway. We speculate that the administration of TUDC might be one of the potential strategies for the hepatotoxicity caused by TGZ.
Nonaka
Michihiro
M
Department of Medicine, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan.
Tazuma
Susumu
S
Hyogo
Hideyuki
H
Kanno
Keishi
K
Chayama
Kazuaki
K
D017209:Apoptosis / Q000187:drug effects*; D002070:Butadienes / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002839:Chromans / Q000633:toxicity*; D019610:Cytoprotection; D005999:Glycochenodeoxycholic Acid / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008024:Ligands; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D013655:Taurochenodeoxycholic Acid / Q000378:metabolism*; D045162:Thiazolidinediones / Q000633:toxicity*; D013997:Time Factors; D000077288:Troglitazone; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D002070:Butadienes; D002839:Chromans; D008024:Ligands; D009570:Nitriles; D047495:PPAR gamma; D047428:Protein Kinase Inhibitors; D045162:Thiazolidinediones; C113580:U 0126; D013655:Taurochenodeoxycholic Acid; C031655:ursodoxicoltaurine; D005999:Glycochenodeoxycholic Acid; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; D000077288:Troglitazone