title: Role of tumor necrosis factor α (TNFα) in the onset of fructose-induced nonalcoholic fatty liver disease in mice.
abstract: Tumor necrosis factor α (TNFα) is known to be involved in dysregulation of hepatic lipid metabolism and insulin signaling. However, whether TNFα also plays a casual role in the onset of fructose-induced nonalcoholic fatty liver disease (NAFLD) has not yet been determined. Therefore, wild-type and TNFα receptor 1 (TNFR1)-/- mice were fed with either 30% fructose solution or plain tap water. Hepatic triglycerides, markers of inflammation and ATP concentration as well as plasma ALT levels were determined. Hepatic PAI-1, SREBP-1, FAS mRNA expression was assessed by real-time RT-PCR. Furthermore, lipid peroxidation and indices of insulin resistance were determined in liver tissue and plasma. In comparison to water controls, chronic intake of 30% fructose solution caused a significant ∼5-fold increase in triglyceride accumulation and neutrophil infiltration in livers of wild-type mice and a ∼8-fold increase in plasma ALT levels. In TNFR1-/- mice, hepatic steatosis was attenuated and neutrophil infiltration in the liver as well as plasma ALT levels was similar to water controls. The protective effect of the TNFR1 deletion against the onset of fructose-induced steatosis was associated with increased phospho AMPK and Akt levels, decreased SREBP-1 and FAS expression in the liver and decreased RBP4 plasma levels, whereas hepatic lipid peroxidation, iNOS protein and ATP levels were similar between wild-type and TNFR1-/- mice fed fructose. Taken together, these data suggest that TNFα plays a casual role in the onset of fructose-induced liver damage as well as insulin resistance in mice through signaling cascades downstream of TNFR1.
authors.affiliation: Department of Nutritional Medicine (180 a), University of Hohenheim, 70599 Stuttgart, Germany. ina.bergheim@uni-hohenheim.de
authors.forename: Giridhar
authors.initials: G
authors.lastname: Kanuri
authors.forename: Astrid
authors.initials: A
authors.lastname: Spruss
authors.forename: Sabine
authors.initials: S
authors.lastname: Wagnerberger
authors.forename: Stephan C
authors.initials: SC
authors.lastname: Bischoff
authors.forename: Ina
authors.initials: I
authors.lastname: Bergheim
mesh_terms: D000818:Animals; D005234:Fatty Liver / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D005632:Fructose / Q000008:administration & dosage*; D050356:Lipid Metabolism; D015227:Lipid Peroxidation; D008099:Liver / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008815:Mice, Inbred Strains; D065626:Non-alcoholic Fatty Liver Disease; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics / Q000378:metabolism; D058258:Serpin E2 / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000502:physiology*; D019014:fas Receptor / Q000378:metabolism
chemical_list: C491899:Fas protein, mouse; D047888:Receptors, Tumor Necrosis Factor, Type I; D058258:Serpin E2; C511869:Serpine2 protein, mouse; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; C506236:Tnfrsf1a protein, mouse; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D005632:Fructose