title: S-adenosylhomocysteine sensitizes to TNF-alpha hepatotoxicity in mice and liver cells: a possible etiological factor in alcoholic liver disease.
abstract: In alcoholic liver disease, tumor necrosis factor-alpha (TNFalpha) is a critical effector molecule, and abnormal methionine metabolism is a fundamental acquired metabolic abnormality. Although hepatocytes are resistant to TNFalpha-induced killing under normal circumstances, previous studies have shown that primary hepatocytes from rats chronically fed alcohol have increased TNFalpha cytotoxicity. Therefore, there must be mechanisms by which chronic alcohol exposure "sensitizes" to TNFalpha hepatotoxicity. S-adenosylhomocysteine (SAH) is product of methionine in transsulfuration pathway and a potent competitive inhibitor of most methyltransferases. In this study, we investigated the effects of increased SAH levels on TNFalpha hepatotoxicity. Our results demonstrated that chronic alcohol consumption in mice not only decreased hepatic S-adenosylmethionine levels but also increased hepatic SAH levels, which resulted in a significantly decreased S-adenosylmethionine-to-SAH ratio. This was associated with significant increases in hepatic TNFalpha levels, caspase-8 activity, and cell death. In vitro studies demonstrated that SAH-enhancing agents sensitized hepatocytes to TNFalpha killing, and the death was associated with increased caspase-8 activity, which was blocked by a caspase-8 inhibitor. In addition, increased intracellular SAH levels had no effect on nuclear factor kappaB activity induced by TNFalpha. In conclusion, these results provide a new link between abnormal methionine metabolism and abnormal TNFalpha metabolism in alcoholic liver disease. Increased SAH is a potent and clinically relevant sensitizer to TNFalpha hepatotoxicity. These data further support improving the S-adenosylmethionine-to-SAH ratio and removal of intracellular SAH as potential therapeutic options in alcoholic liver disease.
authors.affiliation: Department of Medicine, University of Louisville College of Medicine, Louisville, KY, USA.
authors.forename: Zhenyuan
authors.initials: Z
authors.lastname: Song
authors.forename: Zhanxiang
authors.initials: Z
authors.lastname: Zhou
authors.forename: Silvia
authors.initials: S
authors.lastname: Uriarte
authors.forename: Lipeng
authors.initials: L
authors.lastname: Wang
authors.forename: Y James
authors.initials: YJ
authors.lastname: Kang
authors.forename: Theresa
authors.initials: T
authors.lastname: Chen
authors.forename: Shirish
authors.initials: S
authors.lastname: Barve
authors.forename: Craig J
authors.initials: CJ
authors.lastname: McClain
mesh_terms: D000241:Adenosine / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D006528:Carcinoma, Hepatocellular; D053181:Caspase 8; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D006710:Homocysteine / Q000494:pharmacology; D006801:Humans; D008108:Liver Diseases, Alcoholic / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D008745:Methylation / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D012435:S-Adenosylhomocysteine / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000633:toxicity*
chemical_list: D000970:Antineoplastic Agents; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D006710:Homocysteine; D012435:S-Adenosylhomocysteine; C505530:CASP8 protein, human; C505526:Casp8 protein, mouse; D053181:Caspase 8; D020169:Caspases; D000241:Adenosine