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Prevention of bile acid–induced apoptosis by betaine in rat liver
Author(s) -
Graf Dirk,
Kurz Anna Kordelia,
Reinehr Roland,
Fischer Richard,
Kircheis Gerald,
Häussinger Dieter
Publication year - 2002
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1053/jhep.2002.35536
Subject(s) - betaine , apoptosis , bile acid , chemistry , medicine , gastroenterology , microbiology and biotechnology , biochemistry , biology
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.