Skip to main content
Biochemical Journal logoLink to Biochemical Journal
. 1987 Dec 1;248(2):429–437. doi: 10.1042/bj2480429

Stimulation of glycogen synthesis and lipogenesis by glutamine in isolated rat hepatocytes.

A Lavoinne 1, A Baquet 1, L Hue 1
PMCID: PMC1148559  PMID: 3124812

Abstract

Glutamine stimulated glycogen synthesis and lactate production in hepatocytes from overnight-fasted normal and diabetic rats. The effect, which was half-maximal with about 3 mM-glutamine, depended on glucose concentration and was maximal below 10 mM-glucose. beta-2-Aminobicyclo[2.2.1.]heptane-2-carboxylic acid, an analogue of leucine, stimulated glutaminase flux, but inhibited the stimulation of glycogen synthesis by glutamine. Various purine analogues and inhibitors of purine synthesis were found to inhibit glycogen synthesis from glucose, but they did not abolish the stimulatory effect of glutamine on glycogen synthesis. The correlation between the rate of glycogen synthesis and synthase activity suggested that the stimulation of glycogen synthesis by glutamine depended solely on the activation of glycogen synthase. This activation of synthase was not due to a change in total synthase, nor was it caused by a faster inactivation of glycogen phosphorylase, as was the case after glucose. It could, however, result from a stimulation of synthase phosphatase, since, after the addition of 1 nM-glucagon or 10 nM-vasopressin, glutamine did not interfere with the inactivation of synthase, but did promote its subsequent re-activation. Glutamine was also found to inhibit ketone-body production and to stimulate lipogenesis.

Full text

PDF
429

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bollen M., Hue L., Stalmans W. Effects of glucose on phosphorylase and glycogen synthase in hepatocytes from diabetic rats. Biochem J. 1983 Mar 15;210(3):783–787. doi: 10.1042/bj2100783. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bollen M., Stalmans W. The hepatic defect in glycogen synthesis in chronic diabetes involves the G-component of synthase phosphatase. Biochem J. 1984 Jan 15;217(2):427–434. doi: 10.1042/bj2170427. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bontemps F., Hue L., Hers H. G. Phosphorylation of glucose in isolated rat hepatocytes. Sigmoidal kinetics explained by the activity of glucokinase alone. Biochem J. 1978 Aug 15;174(2):603–611. doi: 10.1042/bj1740603. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Boyd M. E., Albright E. B., Foster D. W., McGarry J. D. In vitro reversal of the fasting state of liver metabolism in the rat. Reevaluation of the roles of insulin and glucose. J Clin Invest. 1981 Jul;68(1):142–152. doi: 10.1172/JCI110230. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Carlson C. A., Kim K. H. Regulation of hepatic acetyl coenzyme A carboxylase by phosphorylation and dephosphorylation. J Biol Chem. 1973 Jan 10;248(1):378–380. [PubMed] [Google Scholar]
  6. Chen K. S., Lardy H. A. Multiple requirements for glycogen synthesis by hepatocytes isolated from fasted rats. J Biol Chem. 1985 Nov 25;260(27):14683–14688. [PubMed] [Google Scholar]
  7. Doperé F., Vanstapel F., Stalmans W. Glycogen-synthase phosphatase activity in rat liver. Two protein components and their requirement for the activation of different types of substrate. Eur J Biochem. 1980 Feb;104(1):137–146. doi: 10.1111/j.1432-1033.1980.tb04409.x. [DOI] [PubMed] [Google Scholar]
  8. Geelen M. J. Restoration of glycogenesis in hepatocytes from starved rats. Life Sci. 1977 Mar 15;20(6):1027–1034. doi: 10.1016/0024-3205(77)90290-9. [DOI] [PubMed] [Google Scholar]
  9. Golden S., Wals P. A., Okajima F., Katz J. Glycogen synthesis by hepatocytes from diabetic rats. Biochem J. 1979 Sep 15;182(3):727–734. doi: 10.1042/bj1820727. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. HENDERSON J. F., KHOO K. Y. ON THE MECHANISM OF FEEDBACK INHIBITION OF PURINE BIOSYNTHESIS DE NOVO IN EHRLICH ASCITES TUMOR CELLS IN VITRO. J Biol Chem. 1965 Jul;240:3104–3109. [PubMed] [Google Scholar]
  11. Harris R. A. Studies on the inhibition of hepatic lipogenesis by N-6,O-2'-dibutyryl adenosine 3',5'-monophosphate. Arch Biochem Biophys. 1975 Jul;169(1):168–180. doi: 10.1016/0003-9861(75)90330-6. [DOI] [PubMed] [Google Scholar]
  12. Hashimoto T., Numa S. Kinetic studies on the reaction mechanism and the citrate activation of liver acetyl coenzyme A carboxylase. Eur J Biochem. 1971 Feb 1;18(3):319–331. doi: 10.1111/j.1432-1033.1971.tb01247.x. [DOI] [PubMed] [Google Scholar]
  13. Hems D. A., Whitton P. D., Taylor E. A. Glycogen synthesis in the perfused liver of the starved rat. Biochem J. 1972 Sep;129(3):529–538. doi: 10.1042/bj1290529. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Hers H. G., Hue L. Gluconeogenesis and related aspects of glycolysis. Annu Rev Biochem. 1983;52:617–653. doi: 10.1146/annurev.bi.52.070183.003153. [DOI] [PubMed] [Google Scholar]
  15. Hers H. G. The control of glycogen metabolism in the liver. Annu Rev Biochem. 1976;45:167–189. doi: 10.1146/annurev.bi.45.070176.001123. [DOI] [PubMed] [Google Scholar]
  16. Hershfield M. S., Seegmiller J. E. Regulation of de novo purine biosynthesis in human lymphoblasts. Coordinate control of proximal (rate-determining) steps and the inosinic acid branch point. J Biol Chem. 1976 Dec 10;251(23):7348–7354. [PubMed] [Google Scholar]
  17. Holland R., Witters L. A., Hardie D. G. Glucagon inhibits fatty acid synthesis in isolated hepatocytes via phosphorylation of acetyl-CoA carboxylase by cyclic-AMP-dependent protein kinase. Eur J Biochem. 1984 Apr 16;140(2):325–333. doi: 10.1111/j.1432-1033.1984.tb08105.x. [DOI] [PubMed] [Google Scholar]
  18. Howard R. B., Widder D. J. Substrate control of glycogen levels in isolated hepatocytes from fed rats. Biochem Biophys Res Commun. 1976 Jan 12;68(1):262–269. doi: 10.1016/0006-291x(76)90038-3. [DOI] [PubMed] [Google Scholar]
  19. 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]
  20. Hue L., Felíu J. E., Hers H. G. Control of gluconeogenesis and of enzymes of glycogen metabolism in isolated rat hepatocytes. A parallel study of the effect of phenylephrine and of glucagon. Biochem J. 1978 Dec 15;176(3):791–797. doi: 10.1042/bj1760791. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Hue L. The role of futile cycles in the regulation of carbohydrate metabolism in the liver. Adv Enzymol Relat Areas Mol Biol. 1981;52:247–331. doi: 10.1002/9780470122976.ch4. [DOI] [PubMed] [Google Scholar]
  22. Imazu M., Strickland W. G., Chrisman T. D., Exton J. H. Phosphorylation and inactivation of liver glycogen synthase by liver protein kinases. J Biol Chem. 1984 Feb 10;259(3):1813–1821. [PubMed] [Google Scholar]
  23. Katz J., Golden S., Wals P. A. Glycogen synthesis by rat hepatocytes. Biochem J. 1979 May 15;180(2):389–402. doi: 10.1042/bj1800389. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. 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]
  25. Katz J., Wals P. A., Golden S., Rognstad R. Recycling of glucose by rat hepatocytes. Eur J Biochem. 1975 Dec 1;60(1):91–101. doi: 10.1111/j.1432-1033.1975.tb20979.x. [DOI] [PubMed] [Google Scholar]
  26. Kilberg M. S., Handlogten M. E., Christensen H. N. Characteristics of an amino acid transport system in rat liver for glutamine, asparagine, histidine, and closely related analogs. J Biol Chem. 1980 May 10;255(9):4011–4019. [PubMed] [Google Scholar]
  27. MacLennan P. A., Brown R. A., Rennie M. J. A positive relationship between protein synthetic rate and intracellular glutamine concentration in perfused rat skeletal muscle. FEBS Lett. 1987 May 4;215(1):187–191. doi: 10.1016/0014-5793(87)80139-4. [DOI] [PubMed] [Google Scholar]
  28. Mersmann H. J., Segal H. L. An on-off mechanism for liver glycogen synthetase activity. Proc Natl Acad Sci U S A. 1967 Oct;58(4):1688–1695. doi: 10.1073/pnas.58.4.1688. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Okajima F., Katz J. Effect of mercaptopicolinic acid and of transaminase inhibitors on glycogen synthesis by rat hepatocytes. Biochem Biophys Res Commun. 1979 Mar 15;87(1):155–162. doi: 10.1016/0006-291x(79)91660-7. [DOI] [PubMed] [Google Scholar]
  30. Pösö A. R., Schworer C. M., Mortimore G. E. Acceleration of proteolysis in perfused rat liver by deletion of glucogenic amino acids: regulatory role of glutamine. Biochem Biophys Res Commun. 1982 Aug 31;107(4):1433–1439. doi: 10.1016/s0006-291x(82)80159-9. [DOI] [PubMed] [Google Scholar]
  31. Rognstad R. Possible role for carbamyl phosphate in the control of liver glycogen synthesis. Biochem Biophys Res Commun. 1985 Jul 16;130(1):229–233. doi: 10.1016/0006-291x(85)90406-1. [DOI] [PubMed] [Google Scholar]
  32. Seglen P. O., Gordon P. B. Amino acid control of autophagic sequestration and protein degradation in isolated rat hepatocytes. J Cell Biol. 1984 Aug;99(2):435–444. doi: 10.1083/jcb.99.2.435. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Seglen P. O., Gordon P. B., Poli A. Amino acid inhibition of the autophagic/lysosomal pathway of protein degradation in isolated rat hepatocytes. Biochim Biophys Acta. 1980 Jun 5;630(1):103–118. doi: 10.1016/0304-4165(80)90141-5. [DOI] [PubMed] [Google Scholar]
  34. Stalmans W., Bollen M., Mvumbi L. Control of glycogen synthesis in health and disease. Diabetes Metab Rev. 1987 Jan;3(1):127–161. doi: 10.1002/dmr.5610030107. [DOI] [PubMed] [Google Scholar]
  35. Stalmans W. The role of the liver in the homeostasis of blood glucose. Curr Top Cell Regul. 1976;11:51–97. doi: 10.1016/b978-0-12-152811-9.50009-2. [DOI] [PubMed] [Google Scholar]
  36. Walli A. K., Siebler G., Zepf E., Schimassek H. Glycogen metabolism in isolated perfused rat liver. Hoppe Seylers Z Physiol Chem. 1974 Mar;355(3):353–362. doi: 10.1515/bchm2.1974.355.1.353. [DOI] [PubMed] [Google Scholar]
  37. Whitton P. D., Hems D. A. Glycogen synthesis in the perfused liver of streptozotocin-diabetic rats. Biochem J. 1975 Aug;150(2):153–165. doi: 10.1042/bj1500153. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Zaleski J., Wilson D. F., Erecinska M. Glutamine metabolism in rat hepatocytes. Stimulation by a nonmetabolizable analog of leucine. J Biol Chem. 1986 Oct 25;261(30):14082–14090. [PubMed] [Google Scholar]
  39. Zaleski J., Wilson D. F., Erecinska M. beta-2-Aminobicyclo-(2.2.1)-heptane-2-carboxylic acid. A new activator of glutaminase in intact rat liver mitochondria. J Biol Chem. 1986 Oct 25;261(30):14091–14094. [PubMed] [Google Scholar]

Articles from Biochemical Journal are provided here courtesy of The Biochemical Society

RESOURCES