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

Abstract

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.

• Authors: Ina Bergheim, Luping Guo, Molly Anne Davis, Jason C Lambert, Juliane I Beier, Ilinca Duveau, James P Luyendyk, Robert A Roth, Gavin E Arteel
• Journal: Gastroenterology (Gastroenterology) Vol. 130 Issue 7 Pg. 2099-112 (Jun 2006) ISSN: 0016-5085 [Print] United States
• PMID: 16762632 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural)

Chemical References

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

Topics

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