ATP-depleting carbohydrates prevent tumor necrosis factor receptor 1-dependent apoptotic and necrotic liver injury in mice

Markus Latta, Gerald Künstle, Rudolf Lucas, Hannes Hentze, Albrecht Wendel

Research output: Contribution to journalArticle

7 Scopus citations

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- γlevels 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.

Original languageEnglish (US)
Pages (from-to)875-883
Number of pages9
JournalJournal of Pharmacology and Experimental Therapeutics
Volume321
Issue number3
DOIs
StatePublished - Jun 2007
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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