Gastroenterology
Volume 136, Issue 7 , Pages 2316-2324.e3 , June 2009

Liver Zonation Occurs Through a β-Catenin–Dependent, c-Myc–Independent Mechanism

  • Zoé D. Burke

      Affiliations

    • Centre for Regenerative Medicine, Department of Biology & Biochemistry, University of Bath, Claverton Down, Bath, UK
  • ,
  • Karen R. Reed

      Affiliations

    • School of Biosciences, University of Cardiff, UK
  • ,
  • Toby J. Phesse

      Affiliations

    • School of Biosciences, University of Cardiff, UK
  • ,
  • Owen J. Sansom

      Affiliations

    • The Beatson Institute, Garscube Estate, Glasgow, UK
  • ,
  • Alan R. Clarke

      Affiliations

    • School of Biosciences, University of Cardiff, UK
    • Corresponding Author InformationAlan Clarke, School of Biosciences, University of Cardiff, Cardiff CFIO 3AX, United Kingdom. fax: (44) 1225 386779
  • ,
  • David Tosh

      Affiliations

    • Centre for Regenerative Medicine, Department of Biology & Biochemistry, University of Bath, Claverton Down, Bath, UK
    • Corresponding Author InformationReprint requests Address requests for reprints to: David Tosh, Centre for Regenerative Medicine, Department of Biology & Biochemistry, University of Bath, Claverton Down, Bath BA2 7AY, United Kingdom. fax: (+44) 1225 386779

Received 10 June 2008 ,Accepted 26 February 2009.

References 

  1. Gebhardt R. Metabolic zonation of the liver: regulation and implications for liver function. Pharmacol Ther. 1992;53:275–354
  2. Tosh D, Albert KGMM, Agius L. Glucagon regulation of gluconeogenesis and ketogenesis in periportal and perivenous rat hepatocytes. Biochem J. 1988;256:197–204
  3. Jungermann K, Keitzmann T. Oxygen: modulator of metabolic zonation and disease of the liver. Hepatol. 2000;31:255–260
  4. Gebhardt R, Lindros K, Lamers WH, et al. Hepatocellular heterogeneity in ammonia metabolism: demonstration of limited colocalization of carbamoylphosphate synthetase and glutamine synthetase. Eur J Cell Biol. 1991;56:464–467
  5. Kikuchi A, Kishida S, Yamamoto H. Regulation of Wnt signaling by protein–protein interaction and post-translational modifications. Exp Mol Med. 2006;38:1–10
  6. Miller JR, Hocking AM, Brown JD, et al. Mechanism and function of signal transduction by the Wnt/beta-catenin and Wnt/Ca2+ pathways. Oncogene. 1999;18:7860–7872
  7. Cadigan K, Nusse R. Wnt signaling: a common theme in animal development. Genes Dev. 1997;11:3286–3305
  8. Pinto D, Clevers H. Wnt, stem cells and cancer in the intestine. Biol Cell. 2005;97:185–196
  9. Ober EA, Verkade H, Field HA, et al. Mesodermal Wnt 2b signaling positively regulates liver specification. Nature. 2006;442:688–691
  10. Monga SP, Monga HK, Tan X, et al. Beta-catenin antisense studies in embryonic liver cultures: role in proliferation, apoptosis, and lineage specification. Gastroenterology. 2003;124:202–216
  11. Hussain SZ, Sneddon T, Tan X, et al. Wnt impacts growth and differentiation in ex vivo liver development. Exp Cell Res. 2004;292:157–169
  12. Taniguchi K, Roberts LR, Aderca IN, et al. Mutational spectrum of beta-catenin, AXIN1 and Axin2 in hepatocellular carcinomas and hepatoblastomas. Oncogene. 2002;21:4863–4871
  13. Nhieu JT, Renard CA, Wei Y, et al. Nuclear accumulation of mutated beta-catenin in hepatocellular carcinoma is associated with increased cell proliferation. Am J Pathol. 2000;155:703–710
  14. Colnot S, Decaens T, Niwa-Kawakita M, et al. Liver-targeted disruption of Apc in mice activates beta-catenin signaling and leads to hepatocellular carcinomas. Proc Natl Acad Sci U S A. 2004;101:17216–17221
  15. Hailfinger S, Jaworski M, Braeuning A, et al. Zonal gene expression in murine liver: lessons from tumors. Hepatology. 2006;43:407–414
  16. Benhamouche S, Decaens T, Godard C, et al. Apc tumor suppressor gene is the “zonation-keeper” of mouse liver. Dev Cell. 2006;10:759–770
  17. Matsushita N, Sogawa K, Ema M, et al. A factor binding to the xenobiotic responsive responsive element (XRE) of P-450 1A1 gene consists of at least 2 helix-loop-helix proteins, Ah receptor and Arnt. J Biol Chem. 1993;268:21002–21006
  18. Shibata H, Toyama K, Shioya H, et al. Rapid colorectal adenoma formation initiated by conditional targeting of the Apc gene. Science. 1997;278:120–123
  19. Ireland H, Kemp R, Houghton C, et al. Inducible cre-mediated control of gene expression in the murine gastrointestinal tract: effect of loss of beta-catenin. Gastroenterology. 2004;126:1236–1246
  20. Muncan V, Sansom OJ, Tertoolen L, et al. Rapid loss of intestinal crypts upon conditional deletion of the Wnt/Tcf-4 target gene c-Myc. Mol Cell Biol. 2006;26:8418–8426
  21. Sansom OJ, Reed KR, Hayes AJ, et al. Loss of Apc in vivo immediately perturbs Wnt signalling, differentiation and migration. Genes and Development. 2004;18:1385–1390
  22. Burke ZD, Shen C-N, Ralphs KL, et al. Characterization of liver function in transdifferentiated hepatocytes. J Cell Physiol. 2006;206:147–159
  23. Reed KR, Athineos D, Meniel VS, et al. B-catenin deficiency, but not Myc deletion, suppresses the immediate phenotypes of APC loss in the liver. Proc Natl Acad Sci U S A. 2008;105:18919–18923
  24. Sansom OJ, Meniel VS, Muncan V, et al. c-Myc deletion rescues Apc deficiency in the small intestine. Nature. 2007;446:676–679
  25. Tan X, Behari J, Cieply B, et al. Conditional deletion of beta-catenin reveals its role in liver growth and regeneration. Gastroenterology. 2006;131:1561–1572
  26. Weiner ID, Miller RT, Verlander JW. Localization of the ammonium transporters, Ph B glycoprotein and Ph C glycoprotein, in the mouse liver. Gastroenterology. 2003;124:1432–1440
  27. Cadoret A, Ovejero C, Terris B, et al. New targets of beta-catenin signalling in the liver are involved in the glutamine metabolism. Oncogene. 2002;21:8293–8301
  28. Loeppen S, Koehle C, Buchmann A, et al. A beta-catenin-dependent pathway regulates expression of cytochrome P450 isoforms in mouse liver tumors. Carcinogenesis. 2005;26:239–248
  29. Tang LY, Deng N, Wang LS, et al. Quantitative phosphoproteome profiling of Wnt3a-mediated signaling network: indicating the involvement of ribonucleoside-diphosphate reductase M2 subunit phosphorylation at residue serine 20 in canonical Wnt signal transduction. Mol Cell Proteomics. 2007;6:1952–1967
  30. Duran J, Navarro-Sabate A, Pujol A, et al. Overexpression of ubiquitous 6-phosphofructo-2-kinase in the liver of transgenic mice results in weight gain. Biochem Biophys Res Commun. 2008;365:291–297
  31. Jungermann K, Katz N. Functional specialization of different hepatocyte populations. Physiol Rev. 1989;69:708–764
  32. Sicklick JK, Li YX, Melhem A, et al. Hedgehog signaling maintains resident hepatic progenitors throughout life. Am J Physiol Gastrointest Liver Physiol. 2006;290:G859–G870
  33. Jung Y, McCall SJ, Li YX, et al. Bile ductules and stromal cells express hedgehog ligands and/or hedgehog target genes in primary biliary cirrhosis. Hepatology. 2007;45:1091–1096
  34. Sicklick JK, Li YX, Jayaraman A, et al. Dysregulation of the Hedgehog pathway in human hepatocarcinogenesis. Carcinogenesis. 2006;27:748–757
  35. Kuschak TI, Kuschak BC, Taylor CL, et al. c-Myc initiates illegitimate replication of the ribonucleotide reductase R2 gene. Oncogene. 2002;21:909–920
  36. Osthus R, Shim H, Kim S, et al. Deregulation of glucose transporter 1 and glycolytic gene expression by c-Myc. J Biol Chem. 2000;275:21797–21800
  37. Zeng G, Awan F, Otruba W, et al. Wnt'er in the liver: expression of Wnt and frizzled genes in mouse. Hepatology. 2007;45:195–204
  38. Schrode W, Mecke D, Gebhardt R. Induction of glutamine synthetase in periportal hepatocytes by co-cultivation with a liver epithelial cell line. Eur J Cell Biol. 1990;53:35–41
  39. Kuo FC, Darnell JE. 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;11:6050–6058
  40. Burke ZD, Tosh D. The Wnt/beta-catenin pathway: master regulator of acinar zonation?. Bioessays. 2006;28:1072–1077
  41. Reya T, Clevers H. Wnt signalling in stem cells and cancer. Nature. 2005;434:843–850
  42. Thompson MD, Monga SP. WNT/beta-catenin signalling in liver health and disease. Hepatology. 2007;45:1298–1305

 Conflicts of interest The authors disclose no conflicts.

 Funding Supported by the Wellcome Trust and Cancer Research UK.

PII: S0016-5085(09)00349-7

doi: 10.1053/j.gastro.2009.02.063

Gastroenterology
Volume 136, Issue 7 , Pages 2316-2324.e3 , June 2009