title: Fructose protects murine hepatocytes from tumor necrosis factor-induced apoptosis by modulating JNK signaling.
abstract: Fructose-induced hepatic ATP depletion prevents TNF-induced apoptosis, whereas it contrarily enhances CD95-induced hepatocyte apoptosis in vitro and in vivo. By contrast, transformed liver cells are not protected against TNF due to metabolic alterations, allowing selective tumor targeting. We analyzed the molecular mechanisms by which fructose modulates cytokine-induced apoptosis. A release of adenosine after fructose-induced ATP depletion, followed by a cAMP response, was demonstrated. Likewise, cAMP and adenosine mimicked per se the modulation by fructose of CD95- and TNF-induced apoptosis. The effects of fructose on cytokine-induced apoptosis were sensitive to inhibition of protein kinase A. Fructose prevented the pro-apoptotic, sustained phase of TNF-induced JNK signaling and thereby blocked bid-mediated activation of the intrinsic mitochondrial apoptosis pathway in a PKA-dependent manner. We explain the dichotomal effects of fructose on CD95- and TNF-induced cell death by the selective requirement of JNK signaling for the latter. These findings provide a mechanistic rationale for the protection of hepatocytes from TNF-induced cell death by pharmacological doses of fructose.
authors.affiliation: Chair of Biochemical Pharmacology, Faculty of Biology, University of Konstanz, Konstanz D-78457, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Speicher
authors.forename: Ulrike A
authors.initials: UA
authors.lastname: Köhler
authors.forename: Alexander
authors.initials: A
authors.lastname: Choukèr
authors.forename: Sabine
authors.initials: S
authors.lastname: Werner
authors.forename: Timo
authors.initials: T
authors.lastname: Weiland
authors.forename: Albrecht
authors.initials: A
authors.lastname: Wendel
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D005632:Fructose / Q000494:pharmacology*; D022781:Hepatocytes; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D051379:Mice; D013549:Sweetening Agents / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D019014:fas Receptor / Q000378:metabolism
chemical_list: D013549:Sweetening Agents; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D005632:Fructose; D000255:Adenosine Triphosphate; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D048670:MAP Kinase Kinase 4
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