Metformin prevents alcohol-induced liver injury in the mouse: Critical role of plasminogen activator inhibitor-1

Gastroenterology. 2006 Jun;130(7):2099-112. doi: 10.1053/j.gastro.2006.03.020.


Background & aims: The biguanide drug metformin has recently been found to improve steatosis and liver damage in animal models and in humans with nonalcoholic steatohepatitis.

Methods: The aim of the present study was to determine whether metformin also prevents steatosis and liver damage in mouse models of acute and chronic alcohol exposure.

Results: Acute ethanol exposure caused a >20-fold increase in hepatic lipids, peaking 12 hours after administration. Metformin treatment significantly blunted the ethanol effect by >60%. Although metformin is a known inducer of AMP kinase (AMPK) activity, the hepatoprotective property of metformin did not correlate with activation of AMPK or of AMPK-dependent pathways. Instead, the protective effects of metformin correlated with complete prevention of the upregulation of plasminogen activator inhibitor (PAI)-1 caused by ethanol. Indeed, a similar protective effect against acute alcohol-induced lipid accumulation was observed in PAI-1-/- mice. Hepatic fat accumulation caused by chronic enteral ethanol feeding was also prevented by metformin or by knocking out PAI-1. Under these conditions, necroinflammatory changes caused by ethanol were also significantly attenuated.

Conclusions: Taken together, these findings suggest a novel mechanism of action for metformin and identify a new role of PAI-1 in hepatic injury caused by ethanol.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Animals, Newborn
  • Biopsy, Needle
  • Cells, Cultured
  • Disease Models, Animal
  • Ethanol
  • Immunohistochemistry
  • Lipoproteins, LDL / metabolism
  • Liver Cirrhosis, Alcoholic / drug therapy*
  • Liver Cirrhosis, Alcoholic / prevention & control
  • Metformin / pharmacology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Plasminogen Activator Inhibitor 1 / genetics
  • Plasminogen Activator Inhibitor 1 / metabolism*
  • RNA / analysis
  • Reverse Transcriptase Polymerase Chain Reaction
  • Risk Factors
  • Sensitivity and Specificity
  • Triglycerides / metabolism


  • Lipoproteins, LDL
  • Plasminogen Activator Inhibitor 1
  • Triglycerides
  • Ethanol
  • RNA
  • Metformin