Metformin protects against the development of fructose-induced steatosis in mice: role of the intestinal barrier function
Metformin protects against the development of fructose-induced steatosis in mice: role of the intestinal barrier function
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DOI：
10.1038/labinvest.2012.75
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发表时间：
2012-07-01
影响因子：
5
通讯作者：
Bergheim, Ina
中科院分区：
文献类型：
--
作者：
Spruss, Astrid;Kanuri, Giridhar;Bergheim, Ina
为了检验二甲双胍预防果糖诱导的脂肪变性的假设，如果是这样，为了阐明潜在的机制，C57 BL/6 J小鼠喂食30%果糖溶液或普通水8周。一些动物在饮水溶液中伴随给予二甲双胍（300 mg/kg体重/天）。虽然长期摄入30%果糖溶液导致肝脏甘油三酯蓄积和血浆丙氨酸氨基转移酶水平显著增加，但在同时给予二甲双胍的果糖喂养小鼠中，果糖的这种作用显著减弱。二甲双胍治疗对果糖诱导的非酒精性脂肪性肝病（NAFLD）发作的保护作用与防止果糖喂养小鼠十二指肠中紧密连接蛋白闭合蛋白和闭合小带1的丢失以及仅喂养果糖的小鼠中发现的细菌内毒素易位增加有关。与这些发现一致，在二甲双胍处理的果糖喂养的动物中，Toll样受体-4依赖性信号级联以及纤溶酶原激活物抑制剂/cMet调节的脂质输出的基因的肝脏表达几乎处于对照水平。总之，这些数据表明二甲双胍不仅通过其对肝脏胰岛素信号传导的直接作用机制保护肝脏免受果糖诱导的NAFLD的发作，而且还通过改变肠通透性和随后的内毒素依赖性肝枯否细胞活化来保护肝脏。实验室调查（2012）92，1020-1032; doi：10.1038/labinvest.2012.75; 2012年4月23日在线发表
To test the hypothesis that metformin protects against fructose-induced steatosis, and if so, to elucidate underlying mechanisms, C57BL/6J mice were either fed 30% fructose solution or plain water for 8 weeks. Some of the animals were concomitantly treated with metformin (300 mg/kg body weight/day) in the drinking solution. While chronic consumption of 30% fructose solution caused a significant increase in hepatic triglyceride accumulation and plasma alanine-aminotransferase levels, this effect of fructose was markedly attenuated in fructose-fed mice concomitantly treatment with metformin. The protective effects of the metformin treatment on the onset of fructose-induced non-alcoholic fatty liver disease (NAFLD) were associated with a protection against the loss of the tight junction proteins occludin and zonula occludens 1 in the duodenum of fructose-fed mice and the increased translocation of bacterial endotoxin found in mice only fed with fructose. In line with these findings, in metformin-treated fructose-fed animals, hepatic expression of genes of the toll-like receptor-4-dependent signalling cascade as well as the plasminogen-activator inhibitor/cMet-regulated lipid export were almost at the level of controls. Taken together, these data suggest that metformin not only protects the liver from the onset of fructose-induced NAFLD through mechanisms involving its direct effects on hepatic insulin signalling but rather through altering intestinal permeability and subsequently the endotoxin-dependent activation of hepatic Kupffer cells. Laboratory Investigation (2012) 92, 1020-1032; doi:10.1038/labinvest.2012.75; published online 23 April 2012