title: Altered response to inflammatory cytokines in hepatic energy metabolism in inducible nitric oxide synthase knockout mice.
abstract: OBJECTIVE
  Production of nitric oxide (NO) in the liver is believed to be a critical factor for carbohydrate and energy metabolism in endotoxin shock. The present study focuses on the involvement of NO produced by inducible nitric oxide synthase (iNOS) in glycogen synthesis and energy metabolism stimulated by insulin.
  
  
  METHODS
  Primary hepatocytes prepared from wild-type and iNOS knockout (iNOS(-/-)) mice were employed.
  
  
  RESULTS
  Incubation of wild-type hepatocytes with a combination of cytokines (interleukin-1beta, tumor necrosis factor-alpha and interferon-gamma) and lipopolysaccharide (cytokines/LPS) inhibited insulin-stimulated glycogen synthesis and adenosine triphosphate (ATP) increase, and decreased the ketone body ratio (KBR) at 8-12 h, concomitant with expression of iNOS protein and NO production. While the glycogen synthesis was suppressed by cytokines/LPS, reduction of the ATP increase and a decrease in KBR by cytokines/LPS were not observed in iNOS(-/-) hepatocytes. Further, N(G)-monomethyl-L-arginine, a NOS inhibitor, reversed the inhibition of ATP increase and decrease in KBR by cytokines/LPS, but not the inhibition of glycogen synthesis. Conversely, addition of S-nitroso-N-acetylpenicillamine, a NO donor, inhibited the insulin-stimulated ATP increase synthesis in iNOS(-/-) hepatocytes, but not the insulin-stimulated glycogen synthesis.
  
  
  CONCLUSIONS
  These results demonstrate that NO mediates the suppression of insulin-stimulated energy metabolism, but not glycogen synthesis, in cytokines/LPS-treated hepatocytes.
authors.affiliation: Third Department of Internal Medicine, Kansai Medical University, Miroguchi 570-8506, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Kitano
authors.forename: Tadayoshi
authors.initials: T
authors.lastname: Okumura
authors.forename: Mikio
authors.initials: M
authors.lastname: Nishizawa
authors.forename: Foo Y
authors.initials: FY
authors.lastname: Liew
authors.forename: Toshihito
authors.initials: T
authors.lastname: Seki
authors.forename: Kyoichi
authors.initials: K
authors.lastname: Inoue
authors.forename: Seiji
authors.initials: S
authors.lastname: Ito
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology*; D004734:Energy Metabolism / Q000187:drug effects / Q000502:physiology*; D006003:Glycogen / Q000378:metabolism; D022781:Hepatocytes / Q000166:cytology / Q000201:enzymology; D007328:Insulin / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000096:biosynthesis; D020030:Nitric Oxide Donors / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000235:genetics*; D052247:Nitric Oxide Synthase Type II; D010396:Penicillamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D016207:Cytokines; D007328:Insulin; D007375:Interleukin-1; D008070:Lipopolysaccharides; D020030:Nitric Oxide Donors; C110881:S-nitro-N-acetylpenicillamine; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D007371:Interferon-gamma; D000255:Adenosine Triphosphate; D006003:Glycogen; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D010396:Penicillamine