ATP-Depleting Carbohydrates Prevent Tumor Necrosis Factor Receptor 1-Dependent Apoptotic and Necrotic Liver Injury in Mice

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 321; no. 3; pp. 875 - 883
• Main Authors: Markus Latta, Gerald Künstle, Rudolf Lucas, Hannes Hentze, Albrecht Wendel
• Format: Journal Article
• Language: English
• Published: United States American Society for Pharmacology and Experimental Therapeutics 01.06.2007
• Subjects: Adenosine - pharmacology; Adenosine Triphosphate - metabolism; Alanine Transaminase - blood; Animals; Apoptosis - drug effects; Caspase 3 - metabolism; Caspase 8 - metabolism; Cell Survival - drug effects; Cells, Cultured; Dactinomycin - pharmacology; Hepatocytes - cytology; Hepatocytes - drug effects; Hepatocytes - metabolism; Hexoses - pharmacology; Interferon-gamma - blood; Interleukin-4 - blood; Lipopolysaccharides - pharmacology; Liver - drug effects; Liver - metabolism; Liver - pathology; Male; Mice; Mice, Inbred BALB C; Models, Biological; Necrosis - prevention & control; NF-kappa B - metabolism; Receptors, Tumor Necrosis Factor, Type I - metabolism; T-Lymphocytes - cytology; T-Lymphocytes - drug effects; T-Lymphocytes - metabolism; Tumor Necrosis Factor-alpha - blood; Tumor Necrosis Factor-alpha - metabolism; Tumor Necrosis Factor-alpha - pharmacology
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.107.119958

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-γ 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-κB 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.