PT - JOURNAL ARTICLE AU - Markus Latta AU - Gerald Künstle AU - Rudolf Lucas AU - Hannes Hentze AU - Albrecht Wendel TI - ATP-Depleting Carbohydrates Prevent Tumor Necrosis Factor Receptor 1-Dependent Apoptotic and Necrotic Liver Injury in Mice AID - 10.1124/jpet.107.119958 DP - 2007 Jun 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 875--883 VI - 321 IP - 3 4099 - http://jpet.aspetjournals.org/content/321/3/875.short 4100 - http://jpet.aspetjournals.org/content/321/3/875.full SO - J Pharmacol Exp Ther2007 Jun 01; 321 AB - 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. The American Society for Pharmacology and Experimental Therapeutics