The Effect of Short Chain Fatty Acid Administration on Hepatic Glucose, Phosphate, Magnesium and Calcium Metabolism

  • Richard L. Veech
  • William L. Gitomer
  • Michael T. King
  • Robert S. Balaban
  • Jonathan L. Costa
  • E. David Eanes
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 194)

Abstract

Intra peritoneal administration of the short chain fatty acids, acetate, propionate and butyrate, in amounts calculated to reach 20 mM in total body water were given to fed and 48 hour starved male Wistar rats. One half hour after administration, the livers were freeze-clamped and the hepatic contents of various intermediary metabolites were measured. The liver content of total glycolytic intermediates was elevated by short chain fatty acids. In fed animals, the portion of glycolysis from fructose 1,6-bisphosphate (FBP) to PEP was elevated 2 to 4 fold. In 48 hour starved animals, where gluconeogenesis is active, the portion of the gluconeogenetic pathway from FBP to glucose was elevated 1.5 to 3.5 fold with the exception of the butyrate treated animals where blood glucose was not elevated. The metabolites of the hexose-monophosphate pathway that were measured, namely 6-phosphogluconate, ribulose 5-phosphate and xyulose 5-phosphate were increased in both fed and starved animals. The free cytoplasmic [NAD+] / [NADH],[NADP+] / [NADPH], and [ξATP] / [ξADP] X [ξPi) ratios were all decreased in both fed and starved animals after short chain fatty acid administration. The liver content of calcium increased 1.2 to 2 fold in fed animals and 2 to 3 fold in starved animals while total liver magnesium was either unchanged or increased only 1.2 times. The liver pyrophosphate (PPi) content increased a minimum of 10 fold in fed animals and over 100 fold in starved animals. In all cases no PPi could be detected in vivo by 31P NMR even though in the starved rats the PPi levels approached those of ATP. The liver content of inorganic Pi increased 1.3 to 1.5 fold in fed animals and 1.5 to 2 fold in starved animals. The total “rapidly metabolizing” Pi pool, that includes adenine and guanine nucleotides, glycolytic and shunt intermediates, Pi and PPi increased 1.3 times in fed animals (from 13.8 umole/g fresh weight) and 1.5 to 1.7 fold in starved animals (from 15.7 umol/g fresh weight). The total phosphate taken up from blood and entering the rapidly turning over pool of liver phosphate ranged between 4 and 12 umols/g of liver. It is concluded that the administration of short chain fatty acids whose activation produces inorganic PPi in the cytoplasm and/or the mitochondria have a profound effect on cellular metabolism by: (a) changing the distribution of energy between the various nucleotide pools such as the free cytoplasmic [NADP+] / [NADPH], [NAD+] / [NADH], and [ξATP] / [ξADP] × [ξPi] ratios, (b) elevating the steady state hepatic content of the metabolites of the hexosemonophosphate pathway and the glycolytic pathway, (c) altering the free cytoplasmic PPi and thus changing blood glucose concentrations according to the relation,
$${{k}_{g}}=\frac{\left[ glucose-6-p \right]\ \left[ Pi \right]}{\left[ glu\operatorname{co}se \right]\ \left[ PPi \right]}=45.9,\ and$$
(d) increasing Pi, Ca and Mg transport into the liver.

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References

  1. 1.
    Shatton, J. B., Shah, H., Williams, A., Morris, H. P., and Weinhouse, S. (1981) Activities and properties of inorganic pyrophosphatase in normal tissues and hepatic tumors of the rat. Cancer Research 41, 1866–1872.PubMedGoogle Scholar
  2. 2.
    Nordlie, R. C. and Arion, W. J. (1964) Evidence for the common identity of glucose 6-phosphatase, inorganic pyrophosphatase and pyrophosphate-glucose phosphotransferase. J. Biol. Chem. 239, 1680–1685.PubMedGoogle Scholar
  3. 3.
    Reeves, R. E. (1976) How useful is the energy in inorganic pyrophosphate? Trends in Biochem. Sci. 1, 53–55.Google Scholar
  4. 4.
    Wood, H. G. (1977) Some reactions in which inorganic pyrophosphate replaces ATP and serves as a source of energy. Fed. Proc. 36, 2197–2205.PubMedGoogle Scholar
  5. 5.
    Bessman, M. J., Lehman, I. R., Simons, E. S., and Kornberg, A. (1958) An enzymatic synthesis of desoxyribonucleic acid. J. Biol. Chem. 233, 171–177.PubMedGoogle Scholar
  6. 6.
    Kornberg, A. (1981) in DNA Replication pp 55–56, W. H. Freeman, San Francisco.Google Scholar
  7. 7.
    Merryfield, M. L. and Lardy, H. A. (1982) Cat+ mediated activation of phosphoenolpyruvate carboxykinase occurs via release of Fe2+ from rat liver mitochondria. J. Biol. Chem. 257, 3628–3655.PubMedGoogle Scholar
  8. 8.
    Konopka, K. and Romslo, I. (1981) Studies on the mechanism of pyrophosphate mediated uptake of iron from transferrin by isolated rat-liver mitochondria. Eur. J. Biochem 117, 239–244.PubMedCrossRefGoogle Scholar
  9. 9.
    Simkiss, K. (1981) Calcium, pyrophosphate and cellular pollution. Trends in Biochem. Sci. 6, 3–5.Google Scholar
  10. 10.
    Chausmer, A. B., Sherman, B. S., and Wallack, S. (1972) The effect of parathyroid hormone on hepatic cell transport of calcium. Endo. 90, 663–672.Google Scholar
  11. 11.
    Rasmussen, H., Nagata, N., Feinblatt, J., and Fast, D. (1968) in “Parathyroid Hormone and Thyrocalcitonin” (P.V. Talmage and L. F. Belanger, eds.) p 299, Exerptor Medica Foundation, Amsterdam.Google Scholar
  12. 12.
    Deluca, H. F. and Sallis, J. D. (1965) in “The Parathyroid Gland” (Gailhard, P. J., Talmage, R. V. and Budy, A. M., eds.) p 181, University of Chicago Press, Chicago.Google Scholar
  13. 13.
    Hems, D. A., Harmon, C. S., and Whitton, P. D. (1975) Inhibition by parathyroid hormone of glycogen synthesis in the perfused rat liver. FEBS Lett. 58, 167–169.PubMedCrossRefGoogle Scholar
  14. 14.
    Moxley, M. A., Bell, N. H., Nagle, S. R., Allen, D. O., and Ashmore, J. (1974) Am. J. Physiol 227, 1058–1061.PubMedGoogle Scholar
  15. 15.
    Talmage, R. V., Weil, C. J. V., and Matthews, J. L. (1981) Calcitonin and Phosphate. Mol. and Cell. Endo. 24, 235–251.Google Scholar
  16. 16.
    Lehninger, A. L., Carafoli, E. and Rossi, C. S. (1967) Energy-linked ion movements in mitochondria Adv. Enzymol. 29, 259.PubMedGoogle Scholar
  17. 17.
    Lenhinger, A. L., Brand, M. D. and Reynafarje, B. (1975) Pathways and stoiciometry of H+ and Ca+ transport coupled to mitochondrial electron transport, in Electron Transfer Chains and Oxidative Phosphorylation ( E. Quagliariello, S. Papa F. Palmieri, E. C. Slater, and N. Siliprandi, eds) pp 329–334, North Holland, Amsterdam.Google Scholar
  18. 18.
    Lawson, J. W. R., Guynn, R. W., Cornell, N. W., and Veech, R. L. (1976) in “Gluconeogenesis” (Hanson, R. W. and Mehlman, M. A., eds.) pp. 481–512, John Wiley, New York.Google Scholar
  19. 19.
    Krebs, H. A. and Mapes, J. P. (1978) Rate-limiting factors in urate synthesis and gluconeogenesis in avian liver. Biochem J. 172, 193.PubMedGoogle Scholar
  20. 20.
    Veech, R. L., Nielsen, R., and Harris, R. L. (1975) in “Frontiers of Pineal Physiology” (Altschule, M. D., ed) pp 177–196, MIT Press, Cambridge, Mass.Google Scholar
  21. 21.
    Ginsburg, E., Solomon, D., Sreeralsan, T., and Freese, E. (1973) Growth inhibition and morphological changes caused by lipophilic acids in mammalian cells. Proc. Natl. Acad. Sci., USA 70, 2457–2461.PubMedCrossRefGoogle Scholar
  22. 22.
    Wright, J. A. (1973) Morphology and growth rate changes in Chinese hamster cells cultured in presence of sodium butyrate Exp. Cell. Res. 78, 456–460.PubMedCrossRefGoogle Scholar
  23. 23.
    L. C., Gruss, R. J., and Allfrey, V. G. (1981) Manifold effects of sodium butyrate on nuclear functions. J. Biol. Chem. 256, 9612–9621.PubMedGoogle Scholar
  24. 24.
    Wollenberger, A., Ristan, O., and Schoffa, G. (1960) Pflugers Archiv. Gesante Menschien Tiere 270, 399–412.CrossRefGoogle Scholar
  25. 25.
    Veech, R. L., Lawson, J. W. R., Cornell, N. W., and Krebs, H. A. (1979) Cytosolic Phosphorylation Potential. J. Biol. Chem. 254, 6538–6547.PubMedGoogle Scholar
  26. 26.
    Reiss, P., Zuurendonk, P., and Veech, R. L. Anal. Biochem. (in press).Google Scholar
  27. 27.
    Cook, G. A., O’Brien, W. E., Wood, H. G., King, M. T., and Veech, R. L. (1978) A rapid enzymatic assay for the measurement of inorganic pyrophosphate. Analytical Biochem. 91, 557–565.CrossRefGoogle Scholar
  28. 28.
    Ackerman, J. J. H., Grove, T. H., Wong, G. G., Gadian, D. G., and Radda, G. K. (1980) Nature 283, 167–170.PubMedCrossRefGoogle Scholar
  29. 29.
    Griffiths, J. R., Stevens, A. N., Gadian, D. G., Iles, R. A., and Porteous, R. (1980) Biochem. Soc. Trans. 8, 641.PubMedGoogle Scholar
  30. 30.
    Balaban, R. S., Gadian, D. G., and Radda, G. K. (1980) Kid. Int. 20, 575–579.CrossRefGoogle Scholar
  31. 31.
    Putnins, R. F. and Yamada, E. W. (1975) Anal. Biochem. 68, 185–195.PubMedCrossRefGoogle Scholar
  32. 32.
    Williamson, D. H., Lund, P., and Krebs, H. A. (1967) The redox state of the free nicotinamide-adenine dinucleotide in the cytoplasm and mitochondria of rat liver. Biochem J. 103, 514–517.PubMedGoogle Scholar
  33. 33.
    Veech, R. L., Eggleston, L. V., and Krebs, H. A. (1969) The redox state of free nicotinamide-adenine dinucleotide phosphate in the cytoplasm of rat liver. Biochem. J. 115, 609–619.PubMedGoogle Scholar
  34. 34.
    Veech, R. L., Raijman, L., Dalziel, K., and Krebs, H. A. (1969) Disequilibrium in the triose phosphate isomerase system in rat liver. Biochem. J. 115, 837–842.PubMedGoogle Scholar
  35. 35.
    Veloso, D., Guynn, R. W., Oskarsson, M., and Veech, R. L. (1973) The concentration of free and bound magnesium in rat tissues. J. Biol. Chem. 248, 4811–4819.PubMedGoogle Scholar
  36. 36.
    Aas, M. and Bremer, J. (1968) Biochem. Biophys. Acta 164, 157–166.PubMedGoogle Scholar
  37. 37.
    Barth, C., Sladek, M., and Decker, K. (1971) Biochim. Biophys. Acta 248, 24–33.PubMedGoogle Scholar
  38. 38.
    Clark, D. G., Rognstad, R., and Katz, J. (1973) Isotopic evidence for futile cycles in liver cells. Biochem. Biophys. Res. Comm. 54, 1141–1148.PubMedCrossRefGoogle Scholar
  39. 39.
    Rognstad, R. and Katz, J. (1972) J. Biol. Chem. 247, 6047.PubMedGoogle Scholar
  40. 40.
    Ray, P. D. (1983) in Biochemistry of Metabolic Processes (Lennon, D., Stratman, W., and Zahlten, R. M., eds. ) pp 111–124.Google Scholar
  41. 41.
    Kauffman, F. C., Brown, J. G., Passonneau, J. V., and Lowry, O. H. (1969) Effects of change in brain metabolism on levels of pentose phosphate pathway intermediates. J. Biol. Chem. 244, 3647–3653.PubMedGoogle Scholar
  42. 42.
    Miller, A. L., Hawkins, R. A., and Veech, R. L. (1975) Decreased rate of glucose utilization by rat brain in vivo after exposure to atmospheres containing high concentrations of CO2. J. Neurochem. 25, 553–558.PubMedCrossRefGoogle Scholar
  43. 43.
    Cady, E. B., Dawson, M. J., Hope, P. L., Tofts, P. S., Costello, A. M., Delpy, D. T., Reynolds, E. O. R., and Wilkie, D. R. (1983) Non-invasive investigation of cerebral metabolism in newborn infants by phosphorus nuclear magnetic resonance spectroscopy. Lancet 1059–1060.Google Scholar
  44. 44.
    Brautbar, N., Leibovici, H., and Massry, S. (1983) On the mechanism of hypophosphatemia during acute hyperventilation: evidence for increased muscle glycolysis. Mineral Electrolyte Metab. 9, 45–50.Google Scholar
  45. 45.
    Haldane, J. B. S., Wigglesworth, V. B., and Woodrow, C. E. (1924) The effect of reaction changes in human inorganic metabolism. Proc. R. Soc. B. 96, 1–12.CrossRefGoogle Scholar
  46. 46.
    Mansour, T. E. (1963) Studies on heart phosphofructokinase. J. Biol. Chem. 238, 2285–2292.Google Scholar
  47. 47.
    Uyeda, K. and Racker, E. (1965) J. Biol. Chem. 240, 4682–4688.PubMedGoogle Scholar
  48. 48.
    Henderson, L. J. (1928) Silliman Lectures, Yale University Press.Google Scholar
  49. 49.
    Bessman, S. P. and Geiger, P. J. (1979) Compartmentation, action, regulation and insulinaction, ìn Cur r. Topics in Cell vir Reg. (Horecker, B. L. and Stadtman, E. L., eds) Acedemic Press, New York.Google Scholar
  50. 50.
    Coll, K. E., Joseph, S. K., Corkey, B. E., and Williamson, J. R. (1982) Determination of matrix free Ca2+ concentration and kinetics of Cat+ efflux in liver and heart mitochondria. J. Biol. Chem. 257. 8696–8704.PubMedGoogle Scholar
  51. 51.
    Zuurendonk, P. F. and Tager, J. M. (1974) Biochem. Biophys. Acta 333, 393–399.PubMedCrossRefGoogle Scholar
  52. 52.
    Woods, H. F., Eggleston, L. V., and Krebs, H. A. (1970) The cause of hepatic accumulation of fructose 1-phosphate on fructose loading. Biochem. J. 119, 501–510.PubMedGoogle Scholar
  53. 53.
    Tenenhouse, A., Meier, R., and Rasmussen, H. (1966) J. Biol. Chem. 241, 1314.PubMedGoogle Scholar
  54. 54.
    Bork, A. B. and Neuman, W. F. (1965) J. Cell. Biol. 36, 567.Google Scholar
  55. 55.
    Carnes, D. L. and Campbell, J. W. (1979) Int. J. Biochem. 27, 239–246.Google Scholar

Copyright information

© Plenum Press, New York 1986

Authors and Affiliations

  • Richard L. Veech
    • 1
  • William L. Gitomer
    • 1
  • Michael T. King
    • 1
  • Robert S. Balaban
    • 2
  • Jonathan L. Costa
    • 3
  • E. David Eanes
    • 4
  1. 1.Laboratory of MetabolismNIAAARockvilleUSA
  2. 2.Laboratory of Kidney and Electrolyte MetabolismNHLBIBethesdaUSA
  3. 3.Clinical Neuropharmacology BranchNIMHBethesdaUSA
  4. 4.Mineralized Tissue Research BranchNIDRBethesdaUSA

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