Skip to main content
SpringerLink
Log in
Book cover

Cirrhosis, Hepatic Encephalopathy, and Ammonium Toxicity pp 47–64Cite as

Nitrogen Metabolism in Normal and Cirrhotic Liver

  • Chapter

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 272))

Abstract

In the intact liver acinus, the pathways of ammonia and glutamine metabolism are embedded into a sophisticated structural and functional organization with metabolic interactions between different hepatocyte populations. This provided a new insight into the role of the liver in maintaining ammonia and bicarbonate homeostasis. A specialized cell population at the hepatic venous outflow of the liver acinus acts as a scavenger for ammonia and probably also for various signal molecules (“perivenous scavenger cell hypothesis”). Mitochondrial glutaminase and carbonic anhydrase are controlling HCO -3 and NH +4 input into carbamoylphosphate synthetase in periportal hepatocytes, thereby adding important targets of urea cycle flux control under physiological and pathological conditions. Chronic and acute liver diseases are associated with disturbances of this structural and functional organization. This results in a new understanding of the pathogenetic mechanism contributing to the development of hyperammonemia, acid-base disturbances and possibly other extrahepatic manifestations in liver cirrhosis.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   84.99
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Häussinger, D. (1990). Nitrogen metabolism in liver: Structured and Functional organization and physiological relevance. Biochem, J., 267,281–290.

    Google Scholar 

  2. Jungermann, K. & Katz, N. (1989). Functional specialization of different hepatocyte populations. Physiol. Rev., 6g, 708–784.

    Google Scholar 

  3. Meijer, A.J., Lamers, W.H. & Chamaleau, R.A.F.M. (1989). Nitrogen metabolism and ornithine cycle function. Physiol Rev., in press.

    Google Scholar 

  4. Häussinger, D., Meijer, A.J., Gerok, W. & Sies, H. (1988). Hepatic nitrogen metabolism and acid-base homeostasis. In: pH homeostasis (Häussinger, D., ed.) pp. 337–377, Academic Press London.

    Google Scholar 

  5. Traber, P.G., Chianale, J. & Gumucio, J.J. (1988). Physiologic significance and regulation of hepatocellular heterogeneity. Gastroenterology 95, 30–43.

    Google Scholar 

  6. Häussinger D. (1983). Hepatocyte heterogeneity in glutamine and ammonia metabolism and the role of an intercellular glutamine cycle during ureogenesis in perfused rat liver. Eur. J. Biochem. 133:269–274.

    Article  PubMed  Google Scholar 

  7. Häussinger, D. & Gerok, W. (1984). Hepatocyte heterogeneity in ammonia metabolism: impairment of glutamine synthetase in CC14 induced liver cell necrosis with no effect on urea synthesis. Chem. Biol. Interact. 48, 191–194.

    Article  PubMed  Google Scholar 

  8. Gebhardt, R., Burger, H.J., Schreiber, K.L. & Mecke, D. (1988). Alterations of hepatic enzyme levels and of acinar distribution of glutamine synthetase in response to experimental liver injury in the rat. Hepatology 8, 822–830.

    Article  PubMed  CAS  Google Scholar 

  9. Gaasbeek-Janzen, J.W., Lamers, W.H., Moorman, A.F.M., De Graaf, A., Los, A.J. & Charles, R. (1984). Immunhistochemical localization of carbamoylphosphate synthetase (ammonia) in adult rat liver. J. Histochem. Cytochem. 32, 557–564.

    Article  PubMed  CAS  Google Scholar 

  10. Saheki, T., Yagi, Y., Sase, M., Nakano, K. & Sato, E. (1983). Immunhistochemical localization of argininosuccinate synthetase in the liver of control and citrullinemic patients. Biomed. Res. 4, 235–238.

    CAS  Google Scholar 

  11. Gebhardt, R. & Mecke, D. (1983). Heterogeneous distribution of glutamine synthetase among rat liver parenchymal cells in situ and in primary culture. Embo. J. 2, 567–572.

    PubMed  CAS  Google Scholar 

  12. Moorman, A.F.M., De Boer, A.J., Geerts, W.J.C., Zande, L.V.D., Lamers, W.H. & Charles, R. (1988). Complementary distribution of carbamoylphosphate synthetase (ammonia) and glutamine synthetase in rat liver acinus is regulated at a pretranslational level. J. Histochem. Cytochem. 36, 751–755.

    Article  PubMed  CAS  Google Scholar 

  13. Gebhardt, R., Ebert, A. & Bauer, G. (1988). Heterogeneous expression of glutamine synthetase mRNA in rat liver parenchyma by in situ hybridization and Northern blot analysis of RNA from periportal and perivenous hepatocytes. FEBS Lett. 241, 89–93.

    Article  PubMed  CAS  Google Scholar 

  14. Häussinger, D. & Gerok, W. (1983). Hepatocyte heterogeneity in glutamate uptake in isolated perfused rat liver. Eur. J. Biochem. 136, 421–425.

    Article  PubMed  Google Scholar 

  15. Stoll, B. & Häussinger, D. (1989). Functional hepatocyte heterogeneity. Vascular oxoglutarate is almost exclusively taken up by perivenous glutamine-synthetase-containing hepatocytes. Eur. J. Biochem. 181, 709–716.

    Article  PubMed  CAS  Google Scholar 

  16. Häussinger, D., Stoll, B., Stehle, T. & Gerok, W. (1989). Hepatocyte heterogeneity in glutamate metabolism and bidirectional transport in isolated perfused rat liver. Eur. J. Biochem. 185, 189–195.

    Article  PubMed  Google Scholar 

  17. Smith, D.D. & Campbell, J.W. (1988). Distribution of glutamine synthetase and carbamoylphosphate synthetase I in vertebrate liver. Proc. Natl. Acad. Sci. 85, 160–164.

    Article  PubMed  CAS  Google Scholar 

  18. Lamers, W.H., Gassbeek Janzen, J.W., te Kortschot, A., Charles, R. & Moorman, A.F.M. (1987). The development of enzymic zonation in liver parenchyma is related to the development of the acinar architecture. Differentiation 35, 228–235.

    Article  PubMed  CAS  Google Scholar 

  19. Sies, H. & Häussinger, D. (1984). Hepatic glutamine and ammonia metabolism. Nitrogen and redox balance and the intercellular glutamine cycle. In: Glutamine Metabolism in Mammalian Tissues (Häussinger, D. & Sies, H., eds.) pp 78–97, Springer Verlag Heidelberg.

    Chapter  Google Scholar 

  20. Lusty, C. (1978). Carbamoylphosphate synthetase I of ratliver mitochondria. Purification, properties and polypeptide molecular weight. Eur. J. Biochem. 85, 373–383.

    Article  PubMed  CAS  Google Scholar 

  21. Meijer, A.J., Lof, C, Ramos, I. & Verhoeven, A.J. (1985). Control of ureogenesis. Eur. J. Biochem. 148, 189–196.

    Article  PubMed  CAS  Google Scholar 

  22. Deuel, T.F., Louie, M. & Lerner, M. (1978). Glutamine synthetase from rat liver J. Biol. Chem. 253, 6111–6118.

    PubMed  CAS  Google Scholar 

  23. Häussinger, D., Weiss, L. & Sies, H. (1975). Activation of pyruvate dehydrogenase during metabolism of ammonium ions in hemoglobin-free perfused rat liver. Eur. J. Biochem. 52, 421–431.

    Article  PubMed  Google Scholar 

  24. Kaiser, S., Gerok, W. & Häussinger, D. (1988). Ammonia and glutamine metabolism in human liver slices: new aspects on the pathogenesis of hyperammonemia in chronic liver disease. Eur. J. Clin. Invest. 18, 535–542.

    Article  PubMed  CAS  Google Scholar 

  25. Cooper, A.J.L., Nieves, E., Coleman, A.E., Filc-DeRicco, S. & Gelbard, A.S. (1987). Short-term metabolic fate of [ N] ammonia in rat liver in vivo. J. Biol. Chem. 262, 1073–1080.

    PubMed  CAS  Google Scholar 

  26. McGivan, J.D., Bradford, N.M., Verhoeven, A.J. & Meijer, A.J. (1984). Liver glutaminase. In: Glutamine Metabolism in Mammalian Tissues (Häussinger, D. & Sies, H., eds.) pp. 122–137, Springer Verlag Heidelberg.

    Chapter  Google Scholar 

  27. McGivan, J.D. (1989). Liver glutamine metabolism. In: Glutamine and Glutamate in Mammals (Kvamme, E., ed.) Vol. 1, pp. 183–202, CRC Press, Inc. Boca Raton.

    Google Scholar 

  28. Joseph, S.K. & McGivan, J.D. (1978). The effect of ammonium chloride and glucagon on the metabolism of glutamine in isolated liver cells from starved rats. Biochim. Biophys. Acta 543, 16–28.

    Article  PubMed  CAS  Google Scholar 

  29. Häussinger, D. & Sies, H. (1979). Hepatic glutamine metabolism under the influence of the portal ammonia concentration in the perfused rat liver. Eur. J. Biochem. 101, 179–184.

    Article  PubMed  Google Scholar 

  30. Häussinger, D., Gerok, W. & Sies, H. (1983). Regulation of flux through glutaminase and glutamine synthetase in isolated perfused rat liver. Biochim. Biophys. Acta 755, 272–278.

    Article  PubMed  Google Scholar 

  31. Verhoeven, A.J., van Iwaarden, J.F., Joseph, S.K. & Meijer, A.J. (1983). Control of liver glutaminase by ammonia and pH. Eur. J. Biochem. 133, 241–244.

    Article  PubMed  CAS  Google Scholar 

  32. McGivan, J.D. & Bradford, N.M. (1983). Characteristics of the activation of glutaminase by ammonia in sonicated rat liver mitochondria. Biochim. Biophys. Acta 759, 296–302.

    Article  PubMed  CAS  Google Scholar 

  33. Häussinger, D., Lang, F., Bauers, K., Stehle, T. & Gerok, W. (1990). Interactions between glutamine metabolism and cell volume regulation. Eur. J. Biochem., 188, 689–695.

    Article  PubMed  Google Scholar 

  34. Häussinger, D. & Stehle, T. (1988). Hepatocyte heterogeneity in response to icosanoids. The perivenous scavenger cell hypothesis. Eur. J. Biochem. 175, 395–403.

    Article  PubMed  Google Scholar 

  35. Häussinger, D., ed. (1988). pH Homeostasis, Academic Press London.

    Google Scholar 

  36. Oliver, J., Koelz, A.M., Costello, J. & Bourke, E. (1977). Acid-base-induced alterations in glutamine metabolism and ureogenesis in perfused muscle and liver of the rat. Eur. J. Clin. Invest. 7, 445–449.

    Article  PubMed  CAS  Google Scholar 

  37. Atkinson, D.E. & Camien, M. (1982). The role of urea synthesis in the removal of metabolic bicarbonate and the regulation of blood pH. Curr. Top. Cell. Reg. 21, 261– 302.

    CAS  Google Scholar 

  38. Atkinson, D.E. & Bourke, E. (1984). The role of ureagenesis in pH homeostasis. Trends Biochem. Sci. 9, 297–300.

    Article  CAS  Google Scholar 

  39. Häussinger, D., Gerok, W. & Sies, H. (1984). Hepatic role in pH regulation: role of the intercellular glutamine cycle. Trends Biochem. Sci. 9, 300–302.

    Article  Google Scholar 

  40. Häussinger, D., Gerok, W. & Sies, H. (1986). The effect of urea synthesis on extracellular pH in isolated perfused rat liver. Biochem. J. 236, 261–265.

    PubMed  Google Scholar 

  41. Häussinger, D., Steeb, R. & Gerok, W. (1990) Ammonium and bicarbonate homeostasis in chronic liver disease. Klin. Wschr. 68, 175–182.

    Article  PubMed  Google Scholar 

  42. Gebhardt, R. & Mecke, D. (1984). Cellular distribution and regulation of glutamine synthetase in liver. In: Glutamine Metabolism in Mammalian Tissues (Häussinger, D. & Sies, H., eds.) pp. 98–121, Springer Verlag Heidelberg.

    Chapter  Google Scholar 

  43. Moormann A.F.M., Vermeulen, J.L.M., Charles, R. & Lamers, W.H. (1989). Localization of ammonia metabolizing enzymes in human liver: ontogenesis of heterogeneity. Hepatology 9, 367–372.

    Article  Google Scholar 

  44. Rubio, V., Ramponi, G. & Grisolia, S. (1981). Carbamoylphosphate synthetase I of human liver. Purification, some properties and immunological cross-reactivity with the rat liver enzyme. Biochim. Biophys. Acta 659, 150–160.

    PubMed  CAS  Google Scholar 

  45. Snodgrass, P.J. & Lund, P. (1984). Allosteric properties of phosphate-activated glutaminase of human liver mitochondria. Biochim. Biophys. Acta 798, 21–27.

    Article  PubMed  CAS  Google Scholar 

  46. Häussinger, D., Kaiser, S., Stehle, T. & Gerok, W. (1986). Liver carbonic anhydrase and urea synthesis. The effect of diuretics. Biochem. Pharmacol. 35, 3317–3322.

    Article  PubMed  Google Scholar 

  47. Ugarte, G., Pino, M.E., Valenzuela, J., & Lorca, F. (1963). Urea cycle enzymatic abnormalities in patients with endogenous hepatic coma. Gastroenterology 45, 182–188.

    PubMed  CAS  Google Scholar 

  48. Kathra, B.S., Smith, R.B., Millikan, W., Sewell, C.W., Warren, W.D. & Rudman, D. (1974). Activities of Krebs-Henseleit enzymes in normal and cirrhotic human liver. J. Lab. Clin. Med. 84, 708–715.

    Google Scholar 

  49. Adibi, S.A., Fekl, W., Langenbeck, U. & Schauder, P., eds. (1984). Branched chain amino acids and ketoacids in health disease. S. Karger Basel New York.

    Google Scholar 

  50. Mendenhall, C.L., Rouster, S., Marshall, L. & Weesner, R. (1986). Am. J. Gastroenterol. 81, 540–543.

    PubMed  CAS  Google Scholar 

  51. Häussinger, D. & Gerok, W. (1984). Regulation of hepatic glutamate metabolism. Role of 2-oxoacids in glutamate release from isolated perfused rat liver. Eur. J. Biochem. 143, 491–497.

    Article  PubMed  Google Scholar 

  52. Häussinger, D., Stehle, T. & Colombo, J.P. (1989). Benzoate stimulates glutamate release from perfused rat liver. Biochem. J. 264, 837–843

    PubMed  Google Scholar 

  53. Ballard, R.A., Vinocur, B., Reynolds, J.W., Wennberg, R.P., Merritt, A., Sweetman, L. & Nyhan, W.L. (1978). Transient hyperammonemia of the preterm infant. New Engl. J. Med. 299, 920–925.

    Article  PubMed  CAS  Google Scholar 

  54. Oster, J.R. & Perez, G.O. (1986). J. Hepatol. 2, 299–306.

    Article  PubMed  CAS  Google Scholar 

  55. Dölle, W. (1965). “Der Säurebasenstoffwechsel bei Leberzirrhose” Dr. A. Hüthig Verlag Heidelberg.

    Google Scholar 

  56. Brosnan, J.T., Vinay, P., Gougoux, A. & Halperin, M.L. (1988). Renal ammonium production and implications for acid-base balance. In: pH Homeostasis (Häussinger, D., ed.) pp. 281–304.

    Google Scholar 

  57. Welbourne, T.C., Weber, M. & Bank, N. (1972). J. Clin. Invest. 51, 1852–1860.

    Article  PubMed  CAS  Google Scholar 

  58. Tizianello, A., De Ferrari, G., Garibotto, G., Gurreri, G. & Robaudo, C. (1980). Renal metabolism of amino acids and ammonia in subjects with normal renal function and in patients with chronic renal insufficiency. J. Clin. Invest. 65, 1162–1173.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Medizinische Universitätsklinik, Hugstetterstrasse 55, D-7800, Freiburg, German

    Dieter Häussinger, Rainer Steeb, Stephan Kaiser, Matthias Wettstein, Barbara Stoll & Wolfgang Gerok

Authors
  1. Dieter Häussinger
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rainer Steeb
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Stephan Kaiser
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Matthias Wettstein
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Barbara Stoll
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Wolfgang Gerok
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Instituto de Investigaciones Citológicas, Caja de Ahorros de Valencia, Valencia, Spain

    Santiago Grisolía , Vicente Felipo  & María-Dolores Miñana ,  & 

Rights and permissions

Reprints and permissions

Copyright information

© 1990 Plenum Press, New York

About this chapter

Cite this chapter

Häussinger, D., Steeb, R., Kaiser, S., Wettstein, M., Stoll, B., Gerok, W. (1990). Nitrogen Metabolism in Normal and Cirrhotic Liver. In: Grisolía, S., Felipo, V., Miñana, MD. (eds) Cirrhosis, Hepatic Encephalopathy, and Ammonium Toxicity. Advances in Experimental Medicine and Biology, vol 272. Springer, Boston, MA. https://doi.org/10.1007/978-1-4684-5826-8_3

Download citation

  • DOI: https://doi.org/10.1007/978-1-4684-5826-8_3

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-1-4684-5828-2

  • Online ISBN: 978-1-4684-5826-8

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation