Metformin protects against the development of fructose-induced steatosis in mice: role of the intestinal barrier function

Lab Invest. 2012 Jul;92(7):1020-32. doi: 10.1038/labinvest.2012.75. Epub 2012 Apr 23.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Disease Models, Animal
  • Endotoxins / pharmacokinetics
  • Fatty Liver / genetics
  • Fatty Liver / metabolism
  • Fatty Liver / pathology
  • Fatty Liver / prevention & control*
  • Fructose / administration & dosage
  • Fructose / toxicity*
  • Gene Expression / drug effects
  • Hypoglycemic Agents / pharmacology
  • Insulin Resistance
  • Liver / drug effects
  • Liver / metabolism
  • Liver / pathology
  • Matrix Metalloproteinase 13 / genetics
  • Matrix Metalloproteinase 9 / genetics
  • Metformin / pharmacology*
  • Mice
  • Mice, Inbred C57BL
  • Non-alcoholic Fatty Liver Disease
  • Plasminogen Activator Inhibitor 1 / genetics
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Signal Transduction / drug effects
  • Tissue Inhibitor of Metalloproteinase-1 / metabolism
  • Toll-Like Receptor 4 / genetics
  • Toll-Like Receptor 4 / metabolism
  • Triglycerides / metabolism
  • Tumor Necrosis Factor-alpha / genetics


  • Endotoxins
  • Hypoglycemic Agents
  • Plasminogen Activator Inhibitor 1
  • RNA, Messenger
  • Timp1 protein, mouse
  • Tissue Inhibitor of Metalloproteinase-1
  • Tlr4 protein, mouse
  • Toll-Like Receptor 4
  • Triglycerides
  • Tumor Necrosis Factor-alpha
  • Fructose
  • Metformin
  • Matrix Metalloproteinase 13
  • Mmp13 protein, mouse
  • Matrix Metalloproteinase 9
  • Mmp9 protein, mouse