Abstract
According to current evidence, the mechanism of action of many gluconeogenic hormones involves a rise in intracellular free Ca2+ (Charestet al., 1983; Sistareet al., 1985). There is general agreement that hepatic gluconeogenesis is controlled at several sites in the pathway by Ca2+ -and cAMP-mediated phosphorylations of cytosolic enzymes (Hers and Hue, 1983; Pilkiset al., 1986). Nevertheless, there is a perception that other Ca2+ -linked sites of action may be important; in particular, those which involve mitochondrial enzymes (Leverveet al., 1986; McCormack, 1985; Staddon and Hansford, 1987). The purpose of the study was to evaluate the significance of the stimulation by Ca2+ ofα-ketoglutarate dehydrogenase (McCormack, 1985) and pyruvate dehydrogenase (Oviasu and Whitton, 1984) which occurs following exposure of the liver to glucagon or phenylephrine. The dramatic decrease inα-toglutarate caused by these hormones (Siesset al., 1977) is rather convincingly due to the stimulation ofα-ketoglutarate dehydrogenase. Studies from this laboratory (LaNoueet al., 1983; Schoolwerth and LaNoue, 1983) showed thatα-ketoglutarate is a potent and physiologically important inhibitor of glutamate dehydrogenase. Stimulation ofα-ketoglutarate dehydrogenase relieves inhibition of glutamate dehydrogenase byα-ketoglutarate and, thereby, may stimulate gluconeogenesis from amino acids. Glucagon and phenylephrine are also known to stimulate gluconeogenesis from lactate (Hutsonet al., 1976; Kneeret al., 1979), and to stimulate alcohol oxidation (Ochs and Lardy, 1981) and the malate-aspartate cycle (Kneeret al., 1979; Leverveet al., 1986). These processes do not involve glutamate dehydrogenase but rather aspartate aminotransferase and the glutamate aspartate translocase (Rognstad and Katz, 1970; Williamsonet al., 1971).
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
Charest, R., Blackmore, P. F., Berthon, B., and Exton, J. H., 1983, Changes in free cytosolic Ca2+ in hepatocytes following a-adrenergic stimulation, J. Biol. Chem. 258:8769–8773.
Crompton, M., and Goldston, T. P., 1986, The involvement of calcium in the stimulation of respiration in isolated rat hepatocytes by adrenergic agonists and glucagon, FEBS Lett. 204:198–202.
Hers, H G., and Hue, L., 1983, Gluconeogenesis and related aspects of glycolysis, Ann. Rev. Biochem. 52:617–653.
Hutson, N. J., Brumley, F. T., Assimocopoulos, F. D., Harper, S. C., and Exton, J. H., 1976, Studies on the α-adrenergic activation of hepatic glucose output, J. Biol. Chem. 251:5200–5208.
Kneer, N. M., Wagner, M. J., and Lardy, H. A., 1979, Regulation by calcium of hormonal effects on gluconeogenesis, J. Biol. Chem. ,254:12160–12168.
Krebs, H. A., Mellanby, J., and Williamson, D. H., 1962, The equilibrium constant of the ß-hydroxy-butyric-dehydrogenase system, Biochem. J. 82:96–98.
LaNoue, K. F., and Schoolwerth, A. C., 1979, Metabolite transport in mitochondria, Ann. Rev. Biochem. 48:871–922.
LaNoue, K. F., Schoolwerth, A. C., and Pease, A. J., 1983, Ammonia formation in isolated rat liver mitochondria, J. Biol. Chem. 258:1726–1734.
LaNoue, K. F., Sterniczuk, A., Strzelecki, T., Hreniuk, S., Scaduto, R., Jr., 1987, The effect of mitochondrial Ca2+ on hepatic aspartate formation and gluconeogenic flux. In: Integration of Mitochondrial Function (J. J. Lemasters, C. R. Hackenbrock, R. G. Thurman, and H. V. Esterhoff, eds.), in press.
LaNoue, K. F., Strzelecki, T., and Finch, F., 1984, The effect of glucagon on hepatic respiratory capacity, J. Biol. Chem. 259:4116–4121.
Leverve, X. M., Verhoeven, A. J., Groen, A. K., Meijer, A. J., and Tager, J. M., 1986, The malate/aspartate shuttle and pyruvate kinase as targets involved in the stimulation of gluconeogenesis by phenylephrine, Eur. J. Biochem. 155:551–556.
McCormack, J. G., 1985, Studies on the activation of rat liver pyruvate dehydrogenase and 2-oxoglutarate dehydrogenase by adrenaline and glucagon, Biochem. J. 231:597–608.
Ochs, R. S., and Lardy, H. A., 1981, Catecholamine stimulation of ethanol oxidation by isolated rat hepatocytes, FEBS Lett. 131:119–121.
Oviasu, O. A., and Whitton, P. D., 1984, Hormonal control of pyruvate dehydrogenase activity in rat liver. Biochem. J. 224:181–186.
Parrilla, R., Jimenez, I., Ayuso-Parrilla, M. S., 1975, Glucagon + insulin control of gluconeogenesis in the perfused isolated rat liver. Effects on cellular metabolite distribution, Eur. J. Biochem. 56: 375–383.
Pilkis, S. J., Fox, E., Wolfe, L., Rothbarth, L., Colosia, A., Stewart, H. B., and El-Maghrabi, M. R., 1986, Hormonal modulation of key hepatic regulatory enzymes in the gluconeogenic/glycolytic pathway, Ann. N.Y. Acad. Sci. 478:1–19.
Raval, D. N., and Wolfe, R. G., 1962, Malic dehydrogenase. II. Kinetic studies of the reaction mechanism, Biochemistry 1:263–269.
Rognstad, R., and Katz, J., 1970, Gluconeogenesis in the kidney cortex, Biochem. J. 116:483–491.
Schoolwerth, A. C., and LaNoue, K. F., 1983, Control of ammoniogenesis by α-ketoglutarate in rat kidney mitochondria, Am. J. Physiol. 244:F399–408.
Schworer, C. M., El-Maghrabi, M. R., Pilkis, S. J., and Soderling, T. R., 1985, Phosphorylation of L-type pyruvate kinase by a Ca2+ /calmodulin-dependent protein kinase, J. Biol. Chem. 260: 13018–13022.
Siess, E. A., Brocks, D. G., Lattke, H. K., and Wieland, O. H., 1977, Effect of glucagon on metabolite compartmentation in isolated rat liver cells during gluconeogenesis from lactate, Biochem. J. 166: 225–235.
Sistare, F. D., Picking, R. A., and Haynes, R. C. Jr., 1985, Sensitivity of the response of cytosolic calcium in Quin-2-loaded rat hepatocytes to glucagon, adenine nucleosides, and adenine nucleotides, J. Biol. Chem. 260:12744–12747.
Staddon, J. M., and Hansford, R. G., 1986, 4ß-phorbol 12-myristate 13-acetate attenuates the glucagon-induced increase in cytoplasmic free Ca2+ concentration in isolated rate hepatocytes, Biochem. J. 238:737–743.
Staddon, J. M., and Hansford, R. G., 1987, The glucagon-induced activation of pyruvate dehydrogenase in hepatocytes is diminished by 4ß-phorbol 12-myrisate 13-acetate, Biochem. J. 241:729–735.
Strzelecki, T., Thomas, J. A., Koch, C. D., and Lanoue, K. F., 1984, The effect of hormones on proton compartmentation in hepatocytes, J. Biol. Chem. 259:4122–4129.
Tischler, M. E., Hecht, P., and Williamson, J. R., 1977, Determination of mitochondrial/cytosolic metabolite gradients in isolated rat liver cells by cell disruption, Arch. of Biochem. and Biophys. 181:278–292.
Trinder, P., 1969, Ann. Clin. Biochem. 6:24.
Williamson, J. R., Browning, E. T., Thurman, R. G., and Scholz, R., 1969, Inhibition of glucagon effects in perfused liver by (+) decanoylcarnithine, J. Biol. Chem. 244:5055–5064.
Williamson, J. R., and Corkey, B. E., 1969, Assays of intermediates of the citric acid cycle and related compounds by fluorometric enzyme methods, Method Enzymol. 13:434–513.
Williamson, J. R., Jakob, A., and Refino, C., 1971, Control of the removal of reducing equivalents from the cytosol in perfused liver, J. Biol. Chem. 246:7632–7641.
Zuurendonk, P. F., and Tager, J. M., 1974, Rapid separation of particular components and soluble cytoplasm of isolated rat liver cells, Biochim. et Biophys. Acta 333:393–399.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 1989 Plenum Press, New York
About this chapter
Cite this chapter
Sterniczuk, A., Hreniuk, S., Scaduto, R., LaNoue, K.F. (1989). Effect of Mitochondrial Ca2+ on Hepatic Aspartate Formation and Gluconeogenic Flux. In: Fiskum, G. (eds) Cell Calcium Metabolism. GWUMC Department of Biochemistry Annual Spring Symposia. Springer, Boston, MA. https://doi.org/10.1007/978-1-4684-5598-4_38
Download citation
DOI: https://doi.org/10.1007/978-1-4684-5598-4_38
Publisher Name: Springer, Boston, MA
Print ISBN: 978-1-4684-5600-4
Online ISBN: 978-1-4684-5598-4
eBook Packages: Springer Book Archive