Inhibition of 3-Hydroxy-3-Methyl-Glutaryl-Coenzyme A Reductase Reduces Leukocyte Recruitment and Hepatocyte Apoptosis in Endotoxin-Induced Liver Injury

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Abstract

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.

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