title: ATP-depleting carbohydrates prevent tumor necrosis factor receptor 1-dependent apoptotic and necrotic liver injury in mice.
abstract: We demonstrated previously that depletion of hepatic ATP by endogenous metabolic shunting of phosphate after fructose treatment renders hepatocytes resistant to tumor necrosis factor (TNF)-induced apoptosis. We here address the question whether this principle extends to TNF receptor 1-mediated caspase-independent apoptotic and to necrotic liver injury. As in the apoptotic model of galactosamine/lipopolysaccharide (LPS)-induced liver damage, the necrotic hepatotoxicity initiated by sole high-dose LPS treatment was abrogated after depletion of hepatic ATP. Although systemic TNF and interferon-gamma levels were suppressed, animals still were protected when ATP depletion was initiated after the peak of proinflammatory cytokines upon LPS injection, showing that fructose-induced ATP depletion affects both cytokine release and action. In T cell-dependent necrotic hepatotoxicity elicited by concanavalin A or galactosamine + staphylococcal enterotoxin B, ATP depletion prevented liver injury as well, but here without modulating cytokine release. By attenuating caspase-8 activation, ATP depletion of hepatocytes in vitro impaired TNF receptor signaling by the death-inducing signaling complex, whereas receptor internalization and nuclear factor-kappaB activation upon TNF stimulation were unaffected. These findings demonstrate that sufficient target cell ATP levels are required for the execution of both apoptotic and necrotic TNF-receptor 1-mediated liver cell death.
authors: Biochemical Pharmacology, Faculty of Biology, University of Konstanz, Konstanz, Germany.
authors: Markus
authors: M
authors: Latta
authors: Gerald
authors: G
authors: Künstle
authors: Rudolf
authors: R
authors: Lucas
authors: Hannes
authors: H
authors: Hentze
authors: Albrecht
authors: A
authors: Wendel
mesh_terms: D000241:Adenosine / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003609:Dactinomycin / Q000494:pharmacology; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006601:Hexoses / Q000494:pharmacology*; D007371:Interferon-gamma / Q000097:blood; D015847:Interleukin-4 / Q000097:blood; D008070:Lipopolysaccharides / Q000494:pharmacology; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism; D009336:Necrosis / Q000517:prevention & control; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism*; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000097:blood / Q000378:metabolism / Q000494:pharmacology
chemical_list: D006601:Hexoses; D008070:Lipopolysaccharides; D016328:NF-kappa B; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha; D003609:Dactinomycin; D015847:Interleukin-4; D007371:Interferon-gamma; D000255:Adenosine Triphosphate; D000410:Alanine Transaminase; C505526:Casp8 protein, mouse; D053148:Caspase 3; D053181:Caspase 8; D000241:Adenosine