title: Fat diet and alcohol-induced steatohepatitis after LPS challenge in mice: role of bioactive TNF and Th1 type cytokines.
abstract: Obesity with insulin resistance and alcohol are the most frequent causes of steatohepatitis. This work investigates the contribution of bioactive TNF and Th1 type cytokines in a mouse model of steatohepatitis induced by FAT alone or FAT+EtOH and endotoxin. The extent of liver injury and cytokine activation induced by endotoxin in chronic FAT-fed mice, FAT+EtOH-fed mice, or mice fed standard chow were analyzed. Endotoxin administration to either FAT-fed or FAT+EtOH-fed mice increased serum ALT and AST compared to standard chow mice. Immunoreactive TNF was strongly activated by LPS in FAT-fed and FAT+EtOH-fed mice which presented the highest levels, but low levels were found in standard chow mice. In contrast, bioactive TNF was only present in serum of FAT-fed and in particular the highest levels were found in FAT+EtOH-fed mice. Moreover, soluble TNFR2 but not TNFR1 was found in lower amounts in serum of FAT+EtOH-fed mice compared to FAT-fed mice. Steatohepatitis was associated with increased IL-6, IFN-gamma, and iNOS mRNA and proteins. Data show that a moderately FAT diet and low-dose EtOH concur to generate steatohepatitis and TNF liver expression after LPS. In this model, changes in the regulation of TNF are associated with increased expression of IL-6, IFN-gamma, and iNOS.
authors: Department of Pathology and Immunology, Centre Médical Universitaire, 1 rue Michel-Servet, CH 1211 Geneva 4, Switzerland.
authors: Maria L
authors: ML
authors: Olleros
authors: Maria L
authors: ML
authors: Martin
authors: Dominique
authors: D
authors: Vesin
authors: Agathe L
authors: AL
authors: Fotio
authors: Marie-Laure
authors: ML
authors: Santiago-Raber
authors: Laura
authors: L
authors: Rubbia-Brandt
authors: Laurent
authors: L
authors: Spahr
authors: Antoine
authors: A
authors: Hadengue
authors: Irene
authors: I
authors: Garcia
mesh_terms: D000818:Animals; D016207:Cytokines / Q000502:physiology*; D004041:Dietary Fats / Q000494:pharmacology*; D004195:Disease Models, Animal; D004789:Enzyme Activation; D000431:Ethanol / Q000009:adverse effects*; D005234:Fatty Liver / Q000209:etiology* / Q000473:pathology; D005235:Fatty Liver, Alcoholic / Q000473:pathology / Q000503:physiopathology*; D005260:Female; D007371:Interferon-gamma / Q000502:physiology; D053762:Interleukin-12 Subunit p40 / Q000502:physiology; D015850:Interleukin-6 / Q000502:physiology; D008070:Lipopolysaccharides; D008099:Liver / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D020556:Neutrophil Infiltration; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
chemical_list: D016207:Cytokines; D004041:Dietary Fats; D053762:Interleukin-12 Subunit p40; D015850:Interleukin-6; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D000431:Ethanol; D007371:Interferon-gamma; D009195:Peroxidase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse