Spruss Astrid, Kanuri Giridhar, Wagnerberger Sabine, Haub Synia, Bischoff Stephan C, Bergheim Ina
Department of Nutritional Medicine (180 a), University of Hohenheim, Stuttgart, Germany.
Hepatology. 2009 Oct;50(4):1094-104. doi: 10.1002/hep.23122.
A link between dietary fructose intake, gut-derived endotoxemia, and nonalcoholic fatty liver disease (NAFLD) has been suggested by the results of human and animal studies. To further investigate the role of gut-derived endotoxin in the onset of fructose-induced NAFLD, Toll-like receptor (TLR-) 4-mutant (C3H/HeJ) mice and wildtype (C3H/HouJ) mice were either fed plain water or water enriched with 30% fructose for 8 weeks. Hepatic steatosis, plasma alanine aminotransferase (ALT), and markers of insulin resistance as well as portal endotoxin levels were determined. Hepatic levels of myeloid differentiation factor 88 (MyD88), interferon regulatory factor (IRF) 3 and 7, and tumor necrosis factor alpha (TNFalpha) as well as markers of lipid peroxidation were assessed. Chronic intake of 30% fructose solution caused a significant increase in hepatic steatosis and plasma ALT levels in wildtype animals in comparison to water controls. In fructose-fed TLR-4 mutant mice, hepatic triglyceride accumulation was significantly reduced by approximately 40% in comparison to fructose-fed wildtype mice and plasma ALT levels were at the level of water-fed controls. No difference in portal endotoxin concentration between fructose-fed wildtype and TLR-4-mutant animals was detected. In contrast, hepatic lipid peroxidation, MyD88, and TNFalpha levels were significantly decreased in fructose-fed TLR-4-mutant mice in comparison to fructose-fed wildtype mice, whereas IRF3 and IRF7 expression remained unchanged. Markers of insulin resistance (e.g., plasma TNFalpha, retinol binding protein 4, and hepatic phospho-AKT) were only altered in fructose-fed wildtype animals.
Taken together, these data further support the hypothesis that in mice the onset of fructose-induced NAFLD is associated with intestinal bacterial overgrowth and increased intestinal permeability, subsequently leading to an endotoxin-dependent activation of hepatic Kupffer cells.
人体和动物研究结果提示，膳食果糖摄入、肠道源性内毒素血症与非酒精性脂肪性肝病（NAFLD）之间存在联系。为进一步研究肠道源性内毒素在果糖诱导的NAFLD发病中的作用，将Toll样受体（TLR）-4突变型（C3H/HeJ）小鼠和野生型（C3H/HouJ）小鼠分别给予普通水或富含30%果糖的水，持续8周。测定肝脏脂肪变性、血浆丙氨酸氨基转移酶（ALT）、胰岛素抵抗标志物以及门静脉内毒素水平。评估肝脏中髓样分化因子88（MyD88）、干扰素调节因子（IRF）3和7、肿瘤坏死因子α（TNFα）水平以及脂质过氧化标志物。与饮用普通水的对照组相比，野生型动物长期摄入30%果糖溶液会导致肝脏脂肪变性和血浆ALT水平显著升高。与喂食果糖的野生型小鼠相比，喂食果糖的TLR-4突变型小鼠肝脏甘油三酯积累显著减少约40%，血浆ALT水平与饮用普通水的对照组相当。未检测到喂食果糖的野生型和TLR-4突变型动物门静脉内毒素浓度存在差异。相比之下，与喂食果糖的野生型小鼠相比，喂食果糖的TLR-4突变型小鼠肝脏脂质过氧化、MyD88和TNFα水平显著降低，而IRF3和IRF7表达保持不变。胰岛素抵抗标志物（如血浆TNFα、视黄醇结合蛋白4和肝脏磷酸化AKT）仅在喂食果糖的野生型动物中发生改变。
综上所述，这些数据进一步支持以下假说：在小鼠中，果糖诱导的NAFLD发病与肠道细菌过度生长和肠道通透性增加有关，随后导致肝脏库普弗细胞的内毒素依赖性激活。
