An enhancement of nitric oxide production regulates energy metabolism in rat hepatocytes after a partial hepatectomy.
OBJECTIVE
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-1beta (IL-1beta) 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-1beta. The effects on nitric oxide induction, the ATP content and ketone body ratio (acetoacetate/beta-hydroxybutyrate) were then compared between the partial hepatectomized (PH) and sham-operated (control) rats.


RESULTS
IL-1beta augmented the induction of nitric oxide production two-fold in hepatocytes from the PH rats as compared to the control rats. IL-1beta markedly decreased the ATP content in the PH rats, although IL-1beta also decreased the ATP content in the control rats, but to a lesser extent. IL-1beta 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-1beta 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.
Tu
W
W
First Department of Surgery, Kansai Medical University, Moriguchi, Osaka, Japan.
Kitade
H
H
Kaibori
M
M
Nakagawa
M
M
Inoue
T
T
Kwon
A H
AH
Okumura
T
T
Kamiyama
Y
Y
D000244:Adenosine Diphosphate / Q000378:metabolism; D000249:Adenosine Monophosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001120:Arginine / Q000494:pharmacology; D002478:Cells, Cultured; D004734:Energy Metabolism / Q000187:drug effects; D006498:Hepatectomy; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D007375:Interleukin-1 / Q000494:pharmacology*; D007657:Ketone Bodies / Q000378:metabolism; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D009569:Nitric Oxide / Q000096:biosynthesis*; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000494:pharmacology; D019323:omega-N-Methylarginine / Q000494:pharmacology
D007375:Interleukin-1; D007657:Ketone Bodies; D011994:Recombinant Proteins; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D000249:Adenosine Monophosphate; D000244:Adenosine Diphosphate; D007371:Interferon-gamma; D000255:Adenosine Triphosphate; D001120:Arginine