An enhancement of nitric oxide production regulates energy metabolism in rat hepatocytes after a partial hepatectomy

Abstract

Background/Aims: Infection after a liver resection often results in hepatic failure. Nitric oxide is one of the candidates which has been suspected to cause cellular dysfunction during infection in the liver. We have previously reported that the inflammatory cytokine interleukin-1β (IL-1β) induced the expression of the inducible nitric oxide synthase gene in primary cultured rat hepatocytes. We hypothesized that an enhancement of nitric oxide production after the resection was implicated in a change in liver energy metabolism, thus resulting in liver dysfunction. Methods: In this study, we performed a 70% hepatectomy or a sham operation in rats, and then isolated hepatocytes from the remnant liver by collagenase perfusion. The cultured hepatocytes were treated with cytokines including IL-1β. The effects on nitric oxide induction, the ATP content and ketone body ratio (acetoacetate/β-hydroxybutyrate) were then compared between the partial hepatectomized (PH) and shamoperated (control) rats. Results: IL-1β augmented the induction of nitric oxide production two-fold in hepatocytes from the PH rats as compared to the control rats. IL-1β markedly decreased the ATP content in the PH rats, although IL-1β also decreased the ATP content in the control rats, but to a lesser extent. IL-1β also decreased the ketone body ratio in both groups. The addition of l-arginine further stimulated the inhibition of the ATP levels and the ketone body ratio concomitantly with increased nitric oxide production in the PH rats. N G-monomethyl- l-arginine, an inhibitor of nitric oxide synthase, abolished the effects of IL-1β on the ATP levels and ketone body ratio, as well as on the nitric oxide production. Conclusions: These results demonstrate that the decreased ATP content observed in PH rats resulted from an increase in nitric oxide production. The decrease in ketone body ratio indicates that nitric oxide-induced mitochondrial dysfunction contributes significantly to ATP attenuation in hepatocytes. Therefore, the regulation of nitric oxide induction may be crucial for preventing liver failure after a hepatic resection.