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J Surg Res. 2002 Jul;106(1):31-6.

Increased nitric oxide production in hepatocytes is involved in liver dysfunction following obstructive jaundice.

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  • 1First Department of Surgery, Kansai Medical University, Osaka, 570-8506, Japan.

Abstract

BACKGROUND:

Obstructive jaundice damages critical functions in the liver. However, the mechanisms involved in hepatic dysfunction are obscure. Nitric oxide is implicated in liver injury under various pathological conditions. We previously reported that proinflammatory cytokine interleukin-1beta (IL-1beta) stimulated the production of nitric oxide in hepatocytes, which was associated with mitochondrial dysfunction. Studies were performed to examine whether obstructive jaundice influences the production of nitric oxide in hepatocytes and alters hepatic energy metabolism.

MATERIAL AND METHODS:

Hepatocytes were isolated and cultured from a rat model of obstructive jaundice or sham control. Nitric oxide production, ATP content, and ketone body ratio (acetoacetate/beta-hydroxybutyrate; KBR) were compared between the two groups in the presence of IL-1beta.

RESULTS:

Hepatocytes obtained from obstructive jaundice rats markedly increased the levels of nitric oxide production stimulated by IL-1beta compared with those from sham control. Western blot analysis revealed that the enhancement of nitric oxide production was a posttranslational event, since protein levels of inducible nitric oxide synthase (NOS) were unchanged between the two groups. IL-1beta decreased cellular ATP content in obstructive jaundice but not in sham control. Further, the KBR, which is a marker of mitochondrial redox state, was lower in obstructive jaundice than in sham control. Addition of N(G)-monomethyl-L-arginine, an inhibitor of NOS, abolished the decreases in ATP content and KBR as well as the nitric oxide production.

CONCLUSIONS:

These results indicate that a priming of nitric oxide production following obstructive jaundice is associated with the alteration of hepatic energy metabolism in part through mitochondrial dysfunction. Regulation of nitric oxide production may be a useful therapy for preventing liver dysfunction in obstructive jaundice.

PMID:
12127805
[PubMed - indexed for MEDLINE]
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