title: Prevention of bile acid-induced apoptosis by betaine in rat liver.
abstract: Bile acid-induced apoptosis plays an important role in the pathogenesis of cholestatic liver disease, and its prevention is of therapeutic interest. The effects of betaine were studied on taurolithocholate 3-sulfate (TLCS) and glycochenodeoxycholate (GCDC)-induced apoptosis in rat hepatocytes in vitro and in vivo. Hepatocyte apoptosis, caspase activation, and poly (ADP-ribose) polymerase (PARP) cleavage, which are normally observed in response to both bile acids, were largely prevented after preincubation of hepatocytes with betaine. Betaine uptake was required for this protective effect, which was already observed at betaine concentrations of 1 mmol/L. Betaine did not affect the TLCS-induced membrane trafficking of CD95 and tumor necrosis factor-related apoptosis inducing ligand (TRAIL) receptor 2 to the plasma membrane or the TLCS-induced recruitment of Fas-associated death domain (FADD) and caspase 8 to the CD95 receptor. However, betaine largely prevented cytochrome c release and oxidative stress exerted otherwise by TLCS. Inhibition of caspase 9 strongly blunted TLCS-induced caspase-8 activation. Further betaine did not prevent the TLCS-induced c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (Erk), and p38 mitogen-activated protein kinase (p38(MAPK)) activation or TLCS-induced protein kinase B (PKB) dephosphorylation. The protective betaine effect was insensitive to inhibition of Erks by PD089059, of p38(MAPK) by SB203580, or of phosphatidylinositol 3-kinase (PI3-kinase) by LY294002. Betaine supplementation in the drinking water significantly ameliorated in vivo hepatocyte apoptosis following bile duct ligation. In conclusion, this study identifies betaine as a potent protectant against bile acid-induced apoptosis in vivo and in vitro, and its antiapoptotic action largely resides on an inhibition of the proapoptotic mitochondrial pathway.
authors.affiliation: Department of Gastroenterology, Hepatology and Infectiology, Medizinische Einrichtungen der Heinrich-Heine Universität, Düsseldorf, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Graf
authors.forename: Anna Kordelia
authors.initials: AK
authors.lastname: Kurz
authors.forename: Roland
authors.initials: R
authors.lastname: Reinehr
authors.forename: Richard
authors.initials: R
authors.lastname: Fischer
authors.forename: Gerald
authors.initials: G
authors.lastname: Kircheis
authors.forename: Dieter
authors.initials: D
authors.lastname: Häussinger
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001622:Betaine / Q000494:pharmacology*; D001647:Bile Acids and Salts / Q000494:pharmacology*; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D002779:Cholestasis / Q000188:drug therapy* / Q000473:pathology; D005999:Glycochenodeoxycholic Acid / Q000494:pharmacology; D022781:Hepatocytes / Q000166:cytology; D066298:In Vitro Techniques; D008026:Ligation; D008082:Lipotropic Agents / Q000494:pharmacology*; D008107:Liver Diseases / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013658:Taurolithocholic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D019014:fas Receptor / Q000378:metabolism
chemical_list: D001647:Bile Acids and Salts; D008082:Lipotropic Agents; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; C505644:Tnfrsf10b protein, rat; D019014:fas Receptor; C066776:taurolithocholic acid 3-sulfate; D001622:Betaine; D013658:Taurolithocholic Acid; D005999:Glycochenodeoxycholic Acid