E-Cell System pp 143-155 | Cite as

A Computational Model of the Hepatic Lobule

  • Yasuhiro Naito
Part of the Molecular Biology Intelligence Unit book series (MBIU)


While many inter-organ and intra-organ gene regulations have been found recently, raison d’étre of such regulations are hardly explicated. We aimed liver ammonia detoxification as a prospective target because of its simple histological structure and adopted systems biology approach to elucidate the question. In the mammalian liver, many metabolic systems including ammonia metabolism are heterogeneously processed among hepatocyte position in the lobule.1, 2, 3, 4, 5 Three enzymes that are incorporated in ammonia metabolism are expressed gradually between the periportal zone (influx side) and the pericentral zone (efflux side) in the lobule.6,7 To investigate the cause of the heterogeneous gene expression, a simple eight-compartments model, in which each compartment represented hepatocellular ammonia metabolism by largely enzyme kinetics equations, was developed as a lobule model.8 In silico simulation indicated that regulated enzyme gradient reduced ATP requirement for ammonia detoxification, suggesting that these enzyme gradients by gene regulations improve the fitness of organism by saving energy (ATP consumption).


Glutamine Synthetase Hepatic Lobule Urea Cycle Ammonia Metabolism Pericentral Zone 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Jungermann K, Katz N. Functional specialization of different hepatocyte populations. Physiol Rev 1989; 69(3):708–764.PubMedGoogle Scholar
  2. 2.
    Gebhardt R. Metabolic zonation of the liver: regulation and implications for liver function. Pharmacol Ther 1992; 53(3):275–354.PubMedCrossRefGoogle Scholar
  3. 3.
    Jungermann K, Kietzmann T. Zonation of parenchymal and nonparenchymal metabolism in liver. Annu Rev Nutr 1996; 16179–203.Google Scholar
  4. 4.
    Haussinger D. Liver and systemic pH-regulation. Z Gastroenterol 1992; 30(2):147–150.PubMedGoogle Scholar
  5. 5.
    Meijer AJ, Lamers WH, Chamuleau RA. Nitrogen metabolism and ornithine cycle function. Physiol Rev 1990; 70(3):701–748.PubMedGoogle Scholar
  6. 6.
    Kuo FC, Darnell JE Jr. Evidence that interaction of hepatocytes with the collecting (hepatic) veins triggers position-specific transcription of the glutamine synthetase and ornithine aminotransferase genes in the mouse liver. Mol Cell Biol 1991; 11(12):6050–6058.PubMedGoogle Scholar
  7. 7.
    Kuo FC, Hwu WL, Valle D et al. Colocalization in pericentral hepatocytes in adult mice and similarity in developmental expression pattern of ornithine aminotransferase and glutamine synthetase mRNA. Proc Natl Acad Sci USA 1991; 88(21):9468–9472.PubMedCrossRefGoogle Scholar
  8. 8.
    Ohno H, Naito Y, Nakajima H et al. Construction of biological tissue model based on single-cell model: A computer simulation of metabolic heterogeneity in the liver lobule. Artif Life 2008; 14(1):3–28.PubMedCrossRefGoogle Scholar
  9. 9.
    Schneider W, Siems W, Grune T. Balancing of energy-consuming processes of rat hepatocytes. Cell Biochem Funct 1990; 8(4):227–232.PubMedCrossRefGoogle Scholar
  10. 10.
    Elliott KR, Tipton KF. Product inhibition studies on bovine liver carbamoyl phosphate synthetase. Biochem J 1974; 141(3):817–824.PubMedGoogle Scholar
  11. 11.
    Elliott KR, Tipton KF. Kinetic studies of bovine liver carbamoyl phosphate synthetase. Biochem J 1974; 141(3):807–816.PubMedGoogle Scholar
  12. 12.
    Bachmann C, Krahenbuhl S, Colombo JP. Purification and properties of acetyl-CoA:L-glutamate N-acetyltransferase from human liver. Biochem J 1982; 205(1):123–127.PubMedGoogle Scholar
  13. 13.
    Kohn MC. Propagation of information in MetaNet graph models. J Theor Biol 1992; 154(4):505–517.PubMedCrossRefGoogle Scholar
  14. 14.
    Segel IH. Enzyme Kinetics: Behavior and Analysis of Rapid Equilibrium and Steady State Enzyme Systems. New York: John Wiley and Sons, 1993.Google Scholar
  15. 15.
    Kuchel PW, Roberts DV, Nichol LW. The simulation of the urea cycle: correlation of effects due to inborn errors in the catalytic properties of the enzymes with clinical-biochemical observations. Aust J Exp Biol Med Sci 1977; 55(3):309–326.PubMedCrossRefGoogle Scholar
  16. 16.
    Kohn MC, Tohmaz AS, Giroux KJ et al. Robustness of MetaNet graph models: predicting control of urea production in humans. Biosystems 2002; 65(1):61–78.PubMedCrossRefGoogle Scholar
  17. 17.
    Low SY, Salter M, Knowles RG et al. A quantitative analysis of the control of glutamine catabolism in rat liver cells. Use of selective inhibitors. Biochem J 1993; 295(Pt2)617–624.PubMedGoogle Scholar
  18. 18.
    Christoffels VM, Sassi H, Ruijter JM et al. A mechanistic model for the development and maintenance of portocentral gradients in gene expression in the liver. Hepatology 1999; 29(4):1180–1192.PubMedCrossRefGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media, LLC 2013

Authors and Affiliations

  • Yasuhiro Naito
    • 1
    • 2
  1. 1.Institute for Advanced BiosciencesKeio UniversityTsuruokaJapan
  2. 2.Bioinformatics Program, Graduate School of Media and Governance and Department of Environment and Information StudiesKeio UniversityFujisawaJapan

Personalised recommendations