Department of Nutritional Medicine, University of Hohenheim (180 a), Fruwirthstrasse 12, 70599 Stuttgart, Germany.
Br J Nutr. 2012 Jun;107(12):1727-38. doi: 10.1017/S0007114511004983. Epub 2011 Oct 10.
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.
在动物和人体研究中表明，肠道来源的细菌内毒素可能在非酒精性脂肪性肝病（NAFLD）的发展中起关键作用。在本研究中，我们研究了在果糖诱导的脂肪变性小鼠模型中，肝脏是否也会因其他微生物成分而变得敏感。C57BL/6 小鼠分别用 30%果糖溶液或自来水（对照）喂养 8 周，同时给予或不给予抗生素。检测肝组织 Toll 样受体（TLR）1-9、肿瘤坏死因子-α（TNF-α）、诱导型一氧化氮合酶（iNOS）、髓样分化因子 88（MyD88）和 F4/80 阳性细胞的表达。使用 Western blot、DNA 指纹图谱和 ELISA 分别分析了小肠和大肠微生物 DNA 和血浆视黄醇结合蛋白 4（RBP4）。通过免疫组织化学检测 F4/80 阳性细胞。果糖喂养小鼠肝脏中 TAG 的积累与 TLR1-4 和 6-8 的显著诱导有关。果糖喂养动物的血浆 RBP4 浓度和肝 TNF-α、iNOS、MyD88 基因表达水平以及 F4/80 阳性细胞数均显著高于对照组；然而，抗生素处理的小鼠果糖的这些作用减弱。果糖处理小鼠十二指肠中 occludin 蛋白浓度降低，但在该肠段未发现微生物群的系统性改变。综上所述，这些数据支持以下假设：（1）肠道微生物成分的通透性增加；（2）F4/80 阳性细胞数量增加以及几种 TLR 和依赖途径（如 MyD88 和 iNOS）的诱导可能参与果糖诱导的 NAFLD 的发生。
