Skip to main content
PMC home page
The American Journal of Pathology logoLink to The American Journal of Pathology
. 1998 Apr;152(4):1039–1048.

The gamma-glutamyl transpeptidase gene is transcribed from a different promoter in rat hepatocytes and biliary cells.

A Brouillet 1, N Holic 1, M N Chobert 1, Y Laperche 1
PMCID: PMC1858233  PMID: 9546364

Abstract

Gamma-glutamyl transpeptidase (GGT) activity is commonly used to follow the differentiation of liver precursor cells into the biliary lineage. However, the GGT expression in immature hepatocytes or its induction in adult hepatocytes following diverse carcinogenic or noncarcinogenic treatments has questioned the reliability of GGT expression as a biliary marker. In the present study, we investigated the GGT gene expression from its five different promoters in the late fetal, neonatal, and adult rat liver by Northern blot, reverse transcription-polymerase chain reaction, and in situ hybridization analysis. We show that the GGT activity in the 18-day-old fetus results from the transcription of the gene from the promoter P3 in the hepatocytes. In contrast, the GGT promoter P4 activity appears to be specific of biliary cells in normal as well in cholestatic liver. Thus, sequences unique to the GGT transcripts initiated on these two alternate promoters provide unique molecular probes to discriminate between the biliary and the hepatocytic phenotypes in liver differentiation and cell lineage studies.

Full text

PDF
1039

Images in this article

1042Figure 2
on p.1042
1043Figure 3
on p.1043
1043Figure 4
on p.1043
1044Figure 5
on p.1044
1045Figure 6
on p.1045
1046Figure 7
on p.1046

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Aggerbeck M., Ferry N., Zafrani E. S., Billon M. C., Barouki R., Hanoune J. Adrenergic regulation of glycogenolysis in rat liver after cholestasis. Modulation of the balance between alpha 1 and beta 2 receptors. J Clin Invest. 1983 Mar;71(3):476–486. doi: 10.1172/JCI110792. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Billat C. L., Felix J. M., Jacquot R. L. In vitro and in vivo regulation of hepatic erythropoiesis by erythropoietin and glucocorticoids in the rat fetus. Exp Hematol. 1982 Jan;10(1):133–140. [PubMed] [Google Scholar]
  3. Bradford M. M. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976 May 7;72:248–254. doi: 10.1006/abio.1976.9999. [DOI] [PubMed] [Google Scholar]
  4. Brouillet A., Darbouy M., Okamoto T., Chobert M. N., Lahuna O., Garlatti M., Goodspeed D., Laperche Y. Functional characterization of the rat gamma-glutamyl transpeptidase promoter that is expressed and regulated in the liver and hepatoma cells. J Biol Chem. 1994 May 27;269(21):14878–14884. [PubMed] [Google Scholar]
  5. Darbouy M., Chobert M. N., Lahuna O., Okamoto T., Bonvalet J. P., Farman N., Laperche Y. Tissue-specific expression of multiple gamma-glutamyl transpeptidase mRNAs in rat epithelia. Am J Physiol. 1991 Dec;261(6 Pt 1):C1130–C1137. doi: 10.1152/ajpcell.1991.261.6.C1130. [DOI] [PubMed] [Google Scholar]
  6. Davies R., Edwards R. E., Green J. A., Legg R. F., Snowden R. T., Manson M. M. Antioxidants can delay liver cell maturation which in turn affects gamma-glutamyltranspeptidase expression. Carcinogenesis. 1993 Jan;14(1):47–52. doi: 10.1093/carcin/14.1.47. [DOI] [PubMed] [Google Scholar]
  7. DeBault L. E., Cancilla P. A. gamma-Glutamyl transpeptidase in isolated brain endothelial cells: induction by glial cells in vitro. Science. 1980 Feb 8;207(4431):653–655. doi: 10.1126/science.6101511. [DOI] [PubMed] [Google Scholar]
  8. Elmore L. W., Sirica A. E. Phenotypic characterization of metaplastic intestinal glands and ductular hepatocytes in cholangiofibrotic lesions rapidly induced in the caudate liver lobe of rats treated with furan. Cancer Res. 1991 Oct 15;51(20):5752–5759. [PubMed] [Google Scholar]
  9. Faris R. A., Monfils B. A., Dunsford H. A., Hixson D. C. Antigenic relationship between oval cells and a subpopulation of hepatic foci, nodules, and carcinomas induced by the "resistant hepatocyte" model system. Cancer Res. 1991 Feb 15;51(4):1308–1317. [PubMed] [Google Scholar]
  10. Gerber M. A., Thung S. N. Liver stem cells and development. Lab Invest. 1993 Mar;68(3):253–254. [PubMed] [Google Scholar]
  11. Germain L., Blouin M. J., Marceau N. Biliary epithelial and hepatocytic cell lineage relationships in embryonic rat liver as determined by the differential expression of cytokeratins, alpha-fetoprotein, albumin, and cell surface-exposed components. Cancer Res. 1988 Sep 1;48(17):4909–4918. [PubMed] [Google Scholar]
  12. Griffiths S. A., Good V. M., Gordon L. A., Hudson E. A., Barrett M. C., Munks R. J., Manson M. M. Characterization of a promoter for gamma-glutamyl transpeptidase activated in rat liver in response to aflatoxin B1 and ethoxyquin. Mol Carcinog. 1995 Dec;14(4):251–262. doi: 10.1002/mc.2940140405. [DOI] [PubMed] [Google Scholar]
  13. Hanigan M. H. Expression of gamma-glutamyl transpeptidase provides tumor cells with a selective growth advantage at physiologic concentrations of cyst(e)ine. Carcinogenesis. 1995 Feb;16(2):181–185. doi: 10.1093/carcin/16.2.181. [DOI] [PubMed] [Google Scholar]
  14. Hixson D. C., Faris R. A., Thompson N. L. An antigenic portrait of the liver during carcinogenesis. Pathobiology. 1990;58(2):65–77. doi: 10.1159/000163565. [DOI] [PubMed] [Google Scholar]
  15. Iannaccone P. M., Koizumi J. Pattern and rate of disappearance of gamma-glutamyl transpeptidase activity in fetal and neonatal rat liver. J Histochem Cytochem. 1983 Nov;31(11):1312–1316. doi: 10.1177/31.11.6194205. [DOI] [PubMed] [Google Scholar]
  16. Jagodzinski L. L., Sargent T. D., Yang M., Glackin C., Bonner J. Sequence homology between RNAs encoding rat alpha-fetoprotein and rat serum albumin. Proc Natl Acad Sci U S A. 1981 Jun;78(6):3521–3525. doi: 10.1073/pnas.78.6.3521. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Kurauchi O., Lahuna O., Darbouy M., Aggerbeck M., Chobert M. N., Laperche Y. Organization of the 5' end of the rat gamma-glutamyl transpeptidase gene: structure of a promoter active in the kidney. Biochemistry. 1991 Feb 12;30(6):1618–1623. doi: 10.1021/bi00220a025. [DOI] [PubMed] [Google Scholar]
  18. Lahuna O., Brouillet A., Chobert M. N., Darbouy M., Okamoto T., Laperche Y. Identification of a second promoter which drives the expression of gamma-glutamyl transpeptidase in rat kidney and epididymis. Biochemistry. 1992 Sep 29;31(38):9190–9196. doi: 10.1021/bi00153a011. [DOI] [PubMed] [Google Scholar]
  19. Martín-Sanz P., Cascales M., Boscá L. Fructose 2,6-bisphosphate in isolated foetal hepatocytes. FEBS Lett. 1987 Dec 10;225(1-2):37–42. doi: 10.1016/0014-5793(87)81127-4. [DOI] [PubMed] [Google Scholar]
  20. Mathis G. A., Walls S. A., D'Amico P., Gengo T. F., Sirica A. E. Enzyme profile of rat bile ductular epithelial cells in reference to the resistance phenotype in hepatocarcinogenesis. Hepatology. 1989 Mar;9(3):477–485. doi: 10.1002/hep.1840090323. [DOI] [PubMed] [Google Scholar]
  21. Matsuoka I., Giuili G., Poyard M., Stengel D., Parma J., Guellaen G., Hanoune J. Localization of adenylyl and guanylyl cyclase in rat brain by in situ hybridization: comparison with calmodulin mRNA distribution. J Neurosci. 1992 Sep;12(9):3350–3360. doi: 10.1523/JNEUROSCI.12-09-03350.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Nomura S., Lahuna O., Suzuki T., Brouillet A., Chobert M. N., Laperche Y. A specific distal promoter controls gamma-glutamyl transpeptidase gene expression in undifferentiated rat transformed liver cells. Biochem J. 1997 Sep 1;326(Pt 2):311–320. doi: 10.1042/bj3260311. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Okamoto T., Darbouy M., Brouillet A., Lahuna O., Chobert M. N., Laperche Y. Expression of the rat gamma-glutamyl transpeptidase gene from a specific promoter in the small intestine and in hepatoma cells. Biochemistry. 1994 Sep 27;33(38):11536–11543. doi: 10.1021/bi00204a016. [DOI] [PubMed] [Google Scholar]
  24. Poliard A. M., Bernuau D., Tournier I., Legrès L. G., Schoevaert D., Feldmann G., Sala-Trepat J. M. Cellular analysis by in situ hybridization and immunoperoxidase of alpha-fetoprotein and albumin gene expression in rat liver during the perinatal period. J Cell Biol. 1986 Sep;103(3):777–786. doi: 10.1083/jcb.103.3.777. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Power C. A., Griffiths S. A., Simpson J. L., Laperche Y., Guellaen G., Manson M. M. Induction of gamma-glutamyl transpeptidase mRNA by aflatoxin B1 and ethoxyquin in rat liver. Carcinogenesis. 1987 May;8(5):737–740. doi: 10.1093/carcin/8.5.737. [DOI] [PubMed] [Google Scholar]
  26. Reid L. M., Fiorino A. S., Sigal S. H., Brill S., Holst P. A. Extracellular matrix gradients in the space of Disse: relevance to liver biology. Hepatology. 1992 Jun;15(6):1198–1203. doi: 10.1002/hep.1840150635. [DOI] [PubMed] [Google Scholar]
  27. Shiojiri N., Lemire J. M., Fausto N. Cell lineages and oval cell progenitors in rat liver development. Cancer Res. 1991 May 15;51(10):2611–2620. [PubMed] [Google Scholar]
  28. Sigal S. H., Brill S., Fiorino A. S., Reid L. M. The liver as a stem cell and lineage system. Am J Physiol. 1992 Aug;263(2 Pt 1):G139–G148. doi: 10.1152/ajpgi.1992.263.2.G139. [DOI] [PubMed] [Google Scholar]
  29. Sirica A. E., Elmore L. W., Sano N. Characterization of rat hyperplastic bile ductular epithelial cells in culture and in vivo. Dig Dis Sci. 1991 Apr;36(4):494–501. doi: 10.1007/BF01298882. [DOI] [PubMed] [Google Scholar]
  30. Sirica A. E., Gainey T. W., Mumaw V. R. Ductular hepatocytes. Evidence for a bile ductular cell origin in furan-treated rats. Am J Pathol. 1994 Aug;145(2):375–383. [PMC free article] [PubMed] [Google Scholar]
  31. Sirica A. E., Sattler C. A., Cihla H. P. Characterization of a primary bile ductular cell culture from the livers of rats during extrahepatic cholestasis. Am J Pathol. 1985 Jul;120(1):67–78. [PMC free article] [PubMed] [Google Scholar]
  32. Slott P. A., Liu M. H., Tavoloni N. Origin, pattern, and mechanism of bile duct proliferation following biliary obstruction in the rat. Gastroenterology. 1990 Aug;99(2):466–477. doi: 10.1016/0016-5085(90)91030-a. [DOI] [PubMed] [Google Scholar]
  33. Thorgeirsson S. S., Evarts R. P., Bisgaard H. C., Fujio K., Hu Z. Hepatic stem cell compartment: activation and lineage commitment. Proc Soc Exp Biol Med. 1993 Dec;204(3):253–260. doi: 10.3181/00379727-204-43661. [DOI] [PubMed] [Google Scholar]
  34. Travis J. The search for liver stem cells picks up. Science. 1993 Mar 26;259(5103):1829–1829. doi: 10.1126/science.8456311. [DOI] [PubMed] [Google Scholar]
  35. Vassy J., Kraemer M., Chalumeau M. T., Foucrier J. Development of the fetal rat liver: ultrastructural and stereological study of hepatocytes. Cell Differ. 1988 Jun;24(1):9–24. doi: 10.1016/0045-6039(88)90082-6. [DOI] [PubMed] [Google Scholar]

Articles from The American Journal of Pathology are provided here courtesy of American Society for Investigative Pathology

RESOURCES