The mechanisms by which glycogen metabolism, glycolysis and gluconeogenesis are controlled in the liver both by hormones and by the concentration of glucose are reviewed. The control of glycogen metabolism occurs by phosphorylation and dephosphorylation of both glycogen phosphorylase and glycogen synthase catalysed by various protein kinases and protein phosphatases. The hormonal effect is to stimulate glycogenolysis by the intermediary of cyclic AMP, which activates directly or indirectly the protein kinases. The glucose effect is to activate the protein phosphatase system; this occurs by the direct binding of glucose to glycogen phosphorylase which is then a better substrate for phosphorylase phosphatase and is inactivated. Since phosphorylasea is a strong inhibitor of synthase phosphatase, its disappearance allows the activation of glycogen synthase and the initiation of glycogen synthesis. When glycogen synthesis is intense, the concentrations of UDPG and of glucose 6-phosphate in the liver decrease, allowing a net glucose uptake by the liver. Glucose uptake is indeed the difference between the activities of glucokinase and glucose 6-phosphatase. Since the Km of the latter enzyme is far above the physiological concentration of its substrate, the decrease in glucose 6-phosphate concentration proportionally reduces its activity.
The control of glycolysis and of gluconeogenesis occurs mostly at the level of the interconversion of fructose 6-phosphate and fructose 1,6-bisphosphate under the action of phosphofructokinase 1 and fructose 1,6-bisphosphatase. Fructose 2,6-bisphosphate is a potent stimulator of the first of these two enzymes and an inhibitor of the second. It is formed from fructose 6-phosphate and ATP by phosphofructokinase 2 and hydrolysed by a fructose 2,6-bisphosphatase. These two enzymes are part of a single bifunctional protein which is a substrate for cyclic AMP-dependent protein kinase. Its phosphorylation causes the inactivation of phosphofructokinase 2 and the activation of fructose 2,6-bisphosphatase, resulting in the disappearance of fructose 2,6-bisphosphate. The other major effector of these two enzymes is fructose 6-phosphate, which is the substrate of phosphofructokinase 2 and a potent inhibitor of fructose 2,6-bisphosphatase; these properties allow the formation of fructose 2,6-bisphosphate when the level of glycaemia and secondarily that of fructose 6-phosphate is high.
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Arion, W. J., Wallin, B. K., Lange, A. J. and Ballas, L. M. On the involvement of a glucose 6-phosphate transport system in the function of microsomal glucose 6-phosphatase.Mol. Cell. Biochem. 6 (1975) 75–83
Arion, W. J., Lange, A. J., Walls, H. E. and Ballas L. M. Evidence for the participation of independent translocases for phosphate and glucose 6-phosphate in the microsomal glucose-6-phosphatase system.J. Biol. Chem. 255 (1980) 10396–10406
Berridge, M. J. Inositol trisphosphate and diacylglycerol: two interacting second messengers.Annu. Rev. Biochem. 56 (1987) 159–193
Hers, H. G. Le Métabolisme du Fructose.Editions Arsia, Bruxelles (1957) pp. 200
Hers, H. G. The control of glycogen metabolism in the liver.Annu. Rev. Biochem. 45 (1976) 167–89
Hers, H. G. and Van Schaftingen, E. Fructose 2,6-bisphosphate. Two years after its discovery.Biochem. J. 206 (1982) 1–12
Hers, H. G. and Hue, L. Gluconeogenesis and related aspects of glycolysis.Annu. Rev. Biochem. 52 (1983) 617–653
Hers, H. G., Van Hoof, F. and de Barsy, T. The glycogen storage diseases. In: Scriver, C. R., Beaudet, A. L., Sly W. S. and Valle, D. (eds.),The Metabolic Basis of Inherited Disease, 6th edn., McGraw-Hill, New York, Vol. 1, 1989, 425–452
Kuwajima, M., Newgard, C., Foster, D. W. and McGarry, D. Time course and significance of changes in hepatic fructose 2,6-bisphosphate levels during refeeding of fasted rats.J. Clin. Invest. 74 (1984) 1108–1111
Mvumbi, L., Bollen, M., and Stalmans, W. Calcium ions and glycogen act synergistically as inhibitors of hepatic glycogen-synthase phosphatase.Biochem. J. 232 (1985) 697–704
Nishizuka, Y. The role of protein kinase C in cell surface signal transduction and tumour promotion.Nature 308 (1984) 693–698
Nordlie, R. C., Sukalski, A. and Alvarez, F. L. Responses of glucose 6-phosphate levels to varied glucose loads in the isolated perfused rat liver.J. Biol. Chem. 255 (1980) 1834–1838
Pilkis, S. J., El-Maghrabi, M. R. and Claus, T. H. Hormonal regulation of hepatic gluconeogenesis and glycolysis.Annu. Rev. Biochem. 57 (1988) 755–783
Roach, P. J., Warren, K. R. and Atkinson, D. E. Uridine diphosphate glucose synthase from calf liver: determinants of enzyme activityin vitro.Biochemistry 14 (1975) 544–5450
Seglen, P. O. Autoregulation of glycolysis, respiration, gluconeogenesis and glycogen synthesis in isolated parenchymal rat liver cells under aerobic and anaerobic conditions.Biochem. Biophys. Acta 338 (1974) 317–336
Soskin, S. The liver and carbohydate metabolism.Endocrinology 26 (1940) 297–308
Stalmans, W., Bollen, M., and Mvumbi, L. Control of glycogen synthesis in health and disease.Diabetes/Metab. Rev. 3 (1987) 127–161
Strickland, W. G., Imazu, M., Chrisman, T. D. and Exton, J. H. Regulation of rat liver glycogen synthase. Roles of Ca2+, phosphorylase kinase and phosphorylasea.J. Biol. Chem. 258 (1983) 5490–5497
Tsuboi, K. K., Fukunaga, K. and Petricciani, J. C. Purification and specific kinetic properties of erythrocyte uridine diphosphate glucose pyrophosphorylase.J. Biol. Chem. 244 (1969) 1008–1015
Van Schaftingen, E. Fructose 2,6-bisphosphate.Adv. Enzymol. Relat. Areas Mol. Biol. 59 (1987) 315–395
Van Schaftingen, E. A protein from rat liver confers to glucokinase the property of being antagonistically regulated by fructose 6-phosphate and by fructose 1-phosphate.Eur. J. Biochem. 179 (1989) 179–184
Van Schaftingen, E. and Hers, H. G. Inhibition of fructose-1,6-bisphosphatase by fructose 2,6-bisphosphate.Biochemistry 78 (1981) 2861–2863
Van Schaftingen, E. and Vandercammen, A. Stimulation of glucose phosphorylation by fructose in isolated hepatocyte.Eur. J. Biochem. 179 (1989) 173–177
Van Schaftingen, E., Jett, M. F., Hue, L. and Hers, H. G. Control of liver 6-phosphofructokinase by fructose 2,6-bisphosphate and other effectors.Biochemistry 78 (1981) 3483–3486
Youn, J. H., Youn, M. S. and Bergman, R. N. Synergism of glucose and fructose in net glycogen synthesis in perfused rat livers.J. Biol. Chem. 261 (1986) 15960–15969
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Hers, H.G. Mechanisms of blood glucose homeostasis. J Inherit Metab Dis 13, 395–410 (1990). https://doi.org/10.1007/BF01799497
- Glycogen Synthesis
- Glycogen Phosphorylase
- Glycogen Metabolism