Metformin prevents alcohol-induced liver injury in the mouse: Critical role of plasminogen activator inhibitor-1.
OBJECTIVE
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.
Bergheim
Ina
I
Department of Pharmacology and Toxicology and the James Graham Brown-Cancer Center, University of Louisville Health Sciences Center, Louisville, Kentucky 40292, USA.
Guo
Luping
L
Davis
Molly Anne
MA
Lambert
Jason C
JC
Beier
Juliane I
JI
Duveau
Ilinca
I
Luyendyk
James P
JP
Roth
Robert A
RA
Arteel
Gavin E
GE
D000818:Animals; D000831:Animals, Newborn; D001707:Biopsy, Needle; D002478:Cells, Cultured; D004195:Disease Models, Animal; D000431:Ethanol; D007150:Immunohistochemistry; D008077:Lipoproteins, LDL / Q000378:metabolism; D008104:Liver Cirrhosis, Alcoholic / Q000188:drug therapy* / Q000517:prevention & control; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism*; D012313:RNA / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012307:Risk Factors; D012680:Sensitivity and Specificity; D014280:Triglycerides / Q000378:metabolism
D008077:Lipoproteins, LDL; D017395:Plasminogen Activator Inhibitor 1; D014280:Triglycerides; D000431:Ethanol; D012313:RNA; D008687:Metformin