Inhibition of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase reduces leukocyte recruitment and hepatocyte apoptosis in endotoxin-induced liver injury.
BACKGROUND
Endotoxemia is well known to be associated with an excessive host response to bacteria or microbial compounds, resulting in systemic inflammation and organ injury. The aim of the present study was to examine the effects of simvastatin on endotoxemic liver injury.


METHODS
Male C57BL/6J mice were challenged intraperitoneally with 0.5 mg/kg Escherichia coli-lipopolysaccharide (LPS) and 0.9 g/kg d-galactosamine (Gal). Mice were pretreated with 0.2 mg/kg simvastatin. Lipopolysaccharide/d-Gal-injected mice without simvastatin served as endotoxemic controls, and sham mice served as negative controls. Additional mice were challenged with LPS/d-Gal and co-treated with simvastatin and 10 mg/kg mevalonate to determine the role of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase. After 6 hours of endotoxemia serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities as well as caspase-3 and myeloperoxidase activity were determined.


RESULTS
Endotoxemia caused a substantial hepatocellular injury as indicated by significantly elevated serum ALT and AST levels and hepatocellular apoptosis. Leukocyte infiltration in the liver was significantly elevated in endotoxemic mice. Simvastatin significantly reduced endotoxin-induced hepatocellular damage and apoptosis. Moreover, hepatic accumulation of leukocytes was attenuated by simvastatin in endotoxemic animals. Co-administration of mevalonate abolished protective effects of simvastatin on endotoxin-provoked increases in ALT, AST, and hepatocellular apoptosis as well as leukocyte recruitment.


CONCLUSIONS
Simvastatin has the capacity to prevent endotoxemic liver injury by inhibiting leukocyte infiltration and hepatocellular apoptosis. These protective effects exerted by simvastatin are dependent on the 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase pathway. Thus, simvastatin may represent a potential approach to prevent endotoxemia-associated liver dysfunction.
Slotta
Jan E
JE
Department of Surgery, Malmö University Hospital, Lund University, Malmö, Sweden.
Laschke
Matthias W
MW
Wang
Yusheng
Y
Schilling
Martin K
MK
Menger
Michael D
MD
Thorlacius
Henrik
H
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D019446:Endotoxemia / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007962:Leukocytes / Q000187:drug effects* / Q000502:physiology; D008070:Lipopolysaccharides / Q000633:toxicity; D008099:Liver / Q000187:drug effects / Q000293:injuries* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019821:Simvastatin / Q000494:pharmacology
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008070:Lipopolysaccharides; C440499:lipopolysaccharide, Escherichia coli O111 B4; D019821:Simvastatin; D006903:Hydroxymethylglutaryl CoA Reductases