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. 1998 Mar 1;330(Pt 2):1045–1049. doi: 10.1042/bj3301045

Nitric oxide inhibits glycogen synthesis in isolated rat hepatocytes.

F Sprangers 1, H P Sauerwein 1, J A Romijn 1, G M van Woerkom 1, A J Meijer 1
PMCID: PMC1219243  PMID: 9480928

Abstract

There is increasing evidence for the existence of intrahepatic regulation of glucose metabolism by Kupffer cell products. Nitric oxide (NO) is known to inhibit gluconeogenic flux through pyruvate carboxylase and phosphoenolpyruvate carboxykinase. However, NO may also influence glucose metabolism at other levels. Using hepatocytes from fasted rats incubated with the NO-donor S-nitroso-N-acetylpenicillamine, we have now found that the synthesis of glycogen from glucose is even more sensitive to inhibition by NO than gluconeogenesis. Inhibition of glycogen production by NO was accompanied by a rise in intracellular glucose 6-phosphate and UDPglucose. Activity of glycogen synthase, as measured in extracts of hepatocytes after the cells had been exposed to NO, was decreased. Experiments with gel-filtered liver extracts revealed that inhibition of glycogen synthase was caused by an inhibitory effect of NO on the conversion of glycogen synthase b into glycogen synthase a.

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Selected References

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  1. Albina J. E., Mastrofrancesco B. Modulation of glucose metabolism in macrophages by products of nitric oxide synthase. Am J Physiol. 1993 Jun;264(6 Pt 1):C1594–C1599. doi: 10.1152/ajpcell.1993.264.6.C1594. [DOI] [PubMed] [Google Scholar]
  2. Assimacopoulos-Jeannet F. D., Blackmore P. F., Exton J. H. Studies on alpha-adrenergic activation of hepatic glucose output. Studies on role of calcium in alpha-adrenergic activation of phosphorylase. J Biol Chem. 1977 Apr 25;252(8):2662–2669. [PubMed] [Google Scholar]
  3. Balon T. W., Nadler J. L. Evidence that nitric oxide increases glucose transport in skeletal muscle. J Appl Physiol (1985) 1997 Jan;82(1):359–363. doi: 10.1152/jappl.1997.82.1.359. [DOI] [PubMed] [Google Scholar]
  4. Baquet A., Hue L., Meijer A. J., van Woerkom G. M., Plomp P. J. Swelling of rat hepatocytes stimulates glycogen synthesis. J Biol Chem. 1990 Jan 15;265(2):955–959. [PubMed] [Google Scholar]
  5. Borgs M., Bollen M., Keppens S., Yap S. H., Stalmans W., Vanstapel F. Modulation of basal hepatic glycogenolysis by nitric oxide. Hepatology. 1996 Jun;23(6):1564–1571. doi: 10.1002/hep.510230637. [DOI] [PubMed] [Google Scholar]
  6. Brass E. P., Vetter W. H. Inhibition of glucagon-stimulated glycogenolysis by S-nitroso-N-acetylpenicillamine. Pharmacol Toxicol. 1993 Jun;72(6):369–372. doi: 10.1111/j.1600-0773.1993.tb01346.x. [DOI] [PubMed] [Google Scholar]
  7. Ernest M. J., Kim K. H. Regulation of rat liver glycogen synthetase D. Role of glucose 6-phosphate and enzyme sulfhydryl groups in activity and glycogen binding. J Biol Chem. 1974 Aug 25;249(16):5011–5018. [PubMed] [Google Scholar]
  8. Groen A. K., Sips H. J., Vervoorn R. C., Tager J. M. Intracellular compartmentation and control of alanine metabolism in rat liver parenchymal cells. Eur J Biochem. 1982 Feb;122(1):87–93. doi: 10.1111/j.1432-1033.1982.tb05851.x. [DOI] [PubMed] [Google Scholar]
  9. Hensgens H. E., Meijer A. J., Williamson J. R., Gimpel J. A., Tager J. M. Prolone metabolism in isolated rat liver cells. Biochem J. 1978 Mar 15;170(3):699–707. doi: 10.1042/bj1700699. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Horton R. A., Ceppi E. D., Knowles R. G., Titheradge M. A. Inhibition of hepatic gluconeogenesis by nitric oxide: a comparison with endotoxic shock. Biochem J. 1994 May 1;299(Pt 3):735–739. doi: 10.1042/bj2990735. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Horton R. A., Knowles R. G., Titheradge M. A. Endotoxin causes reciprocal changes in hepatic nitric oxide synthesis, gluconeogenesis, and flux through phosphoenolpyruvate carboxykinase. Biochem Biophys Res Commun. 1994 Oct 28;204(2):659–665. doi: 10.1006/bbrc.1994.2510. [DOI] [PubMed] [Google Scholar]
  12. Hue L., Bontemps F., Hers H. The effects of glucose and of potassium ions on the interconversion of the two forms of glycogen phosphorylase and of glycogen synthetase in isolated rat liver preparations. Biochem J. 1975 Oct;152(1):105–114. doi: 10.1042/bj1520105. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Katz J., Golden S., Wals P. A. Stimulation of hepatic glycogen synthesis by amino acids. Proc Natl Acad Sci U S A. 1976 Oct;73(10):3433–3437. doi: 10.1073/pnas.73.10.3433. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Lavoinne A., Baquet A., Hue L. Stimulation of glycogen synthesis and lipogenesis by glutamine in isolated rat hepatocytes. Biochem J. 1987 Dec 1;248(2):429–437. doi: 10.1042/bj2480429. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Meijer A. J., Baquet A., Gustafson L., van Woerkom G. M., Hue L. Mechanism of activation of liver glycogen synthase by swelling. J Biol Chem. 1992 Mar 25;267(9):5823–5828. [PubMed] [Google Scholar]
  16. Moncada S., Palmer R. M., Higgs E. A. Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol Rev. 1991 Jun;43(2):109–142. [PubMed] [Google Scholar]
  17. Moy J. A., Bates J. N., Fisher R. A. Effects of nitric oxide on platelet-activating factor- and alpha-adrenergic-stimulated vasoconstriction and glycogenolysis in the perfused rat liver. J Biol Chem. 1991 May 5;266(13):8092–8096. [PubMed] [Google Scholar]
  18. Stadler J., Barton D., Beil-Moeller H., Diekmann S., Hierholzer C., Erhard W., Heidecke C. D. Hepatocyte nitric oxide biosynthesis inhibits glucose output and competes with urea synthesis for L-arginine. Am J Physiol. 1995 Jan;268(1 Pt 1):G183–G188. doi: 10.1152/ajpgi.1995.268.1.G183. [DOI] [PubMed] [Google Scholar]
  19. Stadler J., Billiar T. R., Curran R. D., Stuehr D. J., Ochoa J. B., Simmons R. L. Effect of exogenous and endogenous nitric oxide on mitochondrial respiration of rat hepatocytes. Am J Physiol. 1991 May;260(5 Pt 1):C910–C916. doi: 10.1152/ajpcell.1991.260.5.C910. [DOI] [PubMed] [Google Scholar]
  20. Stalmans W., de Wulf H., Hers H. G. The control of liver glycogen synthetase phosphatase by phosphorylase. Eur J Biochem. 1971 Feb;18(4):582–587. doi: 10.1111/j.1432-1033.1971.tb01279.x. [DOI] [PubMed] [Google Scholar]
  21. Titheradge M. A., Knowles R. G., Smith F. S., Horton R. A., Ceppi E. D. Mechanism of inhibition of hepatic gluconeogenesis by bacterial endotoxin: a role for nitric oxide? Biochem Soc Trans. 1995 Nov;23(4):1002–1008. doi: 10.1042/bst0231002. [DOI] [PubMed] [Google Scholar]
  22. Uhing R. J., Janski A. M., Graves D. J. The effect of solvents on nucleotide regulation of glycogen phosphorylase. J Biol Chem. 1979 May 10;254(9):3166–3169. [PubMed] [Google Scholar]
  23. Villar-Palasí C., Guinovart J. J. The role of glucose 6-phosphate in the control of glycogen synthase. FASEB J. 1997 Jun;11(7):544–558. [PubMed] [Google Scholar]
  24. Vom Dahl S., Hallbrucker C., Lang F., Gerok W., Häussinger D. Regulation of liver cell volume and proteolysis by glucagon and insulin. Biochem J. 1991 Sep 15;278(Pt 3):771–777. doi: 10.1042/bj2780771. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Young M. E., Radda G. K., Leighton B. Nitric oxide stimulates glucose transport and metabolism in rat skeletal muscle in vitro. Biochem J. 1997 Feb 15;322(Pt 1):223–228. doi: 10.1042/bj3220223. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. van de Werve G., Hue L., Hers H. G. Hormonal and ionic control of the glycogenolytic cascade in rat liver. Biochem J. 1977 Jan 15;162(1):135–142. doi: 10.1042/bj1620135. [DOI] [PMC free article] [PubMed] [Google Scholar]

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