Toll-like receptors 1-9 are elevated in livers with fructose-induced hepatic steatosis.
Studies in animals and human subjects indicate that gut-derived bacterial endotoxins may play a critical role in the development of non-alcoholic fatty liver disease (NAFLD). In the present study, we investigated if the liver is also sensitised by other microbial components during the onset of fructose-induced steatosis in a mouse model. C57BL/6 mice were either fed with 30 % fructose solution or tap water (control) with or without antibiotics for 8 weeks. Expression of toll-like receptors (TLR)1-9, TNF-α, inducible NO synthase (iNOS), myeloid differentiation factor 88 (MyD88) and number of F4/80 positive cells in the liver were assessed. Occludin protein, DNA of microbiota in the small and large intestine and retinol binding protein 4 (RBP4) in plasma were analysed using Western blot, DNA fingerprinting and ELISA, respectively. F4/80 positive cells were determined by immunohistochemistry. The accumulation of TAG found in the livers of fructose-fed mice was associated with a significant induction of TLR 1-4 and 6-8. Plasma RBP4 concentration and hepatic mRNA expression levels of TNF-α, iNOS, MyD88 and number of F4/80 positive cells of fructose-fed animals were significantly higher than those of controls; however, these effects of fructose were attenuated in antibiotic-treated mice. Whereas protein concentration of occludin was lower in the duodenum of fructose-treated mice, no systematic alterations of microbiota were found in this part of the intestine. Taken together, these data support the hypothesis that (1) an increased intestinal translocation of microbial components and (2) an increased number of F4/80 positive cells and induction of several TLR and dependent pathways (e.g. MyD88 and iNOS) may be involved in the onset of fructose-induced NAFLD.
Department of Nutritional Medicine, University of Hohenheim (180 a), Fruwirthstrasse 12, 70599 Stuttgart, Germany.
Sabine
S
Wagnerberger
Astrid
A
Spruss
Giridhar
G
Kanuri
Valentina
V
Volynets
Carolin
C
Stahl
Stephan C
SC
Bischoff
Ina
I
Bergheim
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000943:Antigens, Differentiation / Q000378:metabolism; D018988:Bacterial Translocation; D004195:Disease Models, Animal; D004386:Duodenum / Q000378:metabolism / Q000382:microbiology; D005234:Fatty Liver / Q000139:chemically induced / Q000378:metabolism* / Q000382:microbiology; D005632:Fructose / Q000009:adverse effects*; D007422:Intestines / Q000382:microbiology*; D008099:Liver / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D054892:Metagenome; D051379:Mice; D008810:Mice, Inbred C57BL; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D065626:Non-alcoholic Fatty Liver Disease; D062793:Occludin; D012333:RNA, Messenger / Q000378:metabolism; D054839:Retinol-Binding Proteins, Plasma / Q000378:metabolism; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000378:metabolism*; D014280:Triglycerides / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
D000900:Anti-Bacterial Agents; D000943:Antigens, Differentiation; D008565:Membrane Proteins; D053594:Myeloid Differentiation Factor 88; C568985:OCLN protein, human; D062793:Occludin; C568986:Ocln protein, mouse; D012333:RNA, Messenger; C502487:Rbp4 protein, mouse; D054839:Retinol-Binding Proteins, Plasma; D051193:Toll-Like Receptors; D014280:Triglycerides; D014409:Tumor Necrosis Factor-alpha; C036763:monocyte-macrophage differentiation antigen; D005632:Fructose; D052247:Nitric Oxide Synthase Type II