Toll-like receptors 1–9 are elevated in livers with fructose-induced hepatic steatosis

• Published in: British journal of nutrition Vol. 107; no. 12; pp. 1727 - 1738
• Main Authors: Wagnerberger, Sabine, Spruss, Astrid, Kanuri, Giridhar, Volynets, Valentina, Stahl, Carolin, Bischoff, Stephan C., Bergheim, Ina
• Format: Journal Article
• Language: English
• Published: Cambridge, UK Cambridge University Press 28.06.2012
• Subjects: animal models; Animals; Anti-Bacterial Agents - pharmacology; Antibiotics; Antigens, Differentiation - metabolism; Bacterial Translocation; Biological and medical sciences; Deoxyribonucleic acid; Diet; Disease Models, Animal; DNA; DNA fingerprinting; Drinking water; duodenum; Duodenum - metabolism; Duodenum - microbiology; Endotoxins; enzyme-linked immunosorbent assay; fatty liver; Fatty Liver - chemically induced; Fatty Liver - metabolism; Fatty Liver - microbiology; Feeding. Feeding behavior; fructose; Fructose - adverse effects; Fundamental and applied biological sciences. Psychology; gene expression; hepatocytes; humans; immunohistochemistry; inducible nitric oxide synthase; Intestines - microbiology; large intestine; liver; Liver - metabolism; Liver diseases; Membrane Proteins - metabolism; messenger RNA; Metagenome; Mice; Mice, Inbred C57BL; Microorganisms; Molecular Nutrition; Myeloid Differentiation Factor 88 - genetics; Myeloid Differentiation Factor 88 - metabolism; Nitric Oxide Synthase Type II - genetics; Nitric Oxide Synthase Type II - metabolism; Non-alcoholic Fatty Liver Disease; Occludin; occludins; retinol-binding protein; Retinol-Binding Proteins, Plasma - metabolism; RNA, Messenger - metabolism; Rodents; Signal Transduction; Sugar; tap water; Toll-like receptors; Toll-Like Receptors - metabolism; Translocation; Triglycerides - metabolism; tumor necrosis factor-alpha; Tumor Necrosis Factor-alpha - genetics; Tumor Necrosis Factor-alpha - metabolism; Vertebrates: anatomy and physiology, studies on body, several organs or systems; Western blotting; Non-alcoholic fatty liver disease; Toll-like receptor; Fructose; Occludin; Vertebrata; Mammalia; Fatty liver; Non alcoholic steatohepatitis; Digestive diseases; Hepatic disease; Toll like receptor
• ISSN: 0007-1145; 1475-2662; 1475-2662
• DOI: 10.1017/S0007114511004983

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.