Histochemistry and Cell Biology

, Volume 128, Issue 5, pp 431–443 | Cite as

Kinetics of albumin- and alpha-fetoprotein-production during rat liver development

  • Abderrahim Elmaouhoub
  • József Dudas
  • Giuliano RamadoriEmail author
Original Paper


Synthesis of most of the plasma proteins is one of the main functions of the hepatocytes. Albumin synthesis is quantitatively the most abundant. In the present study we investigated albumin- and alpha-fetoprotein-gene-expression, and the function of the secretory apparatus during rat liver development. To this purpose we used the method of radioactive biosynthetic labeling of newly synthesized albumin and alpha-fetoprotein (AFP) to monitor the secretory capacity of endodermal cells derived from ventral foregut region (embryonic day 10, E10), and of embryonic and fetal hepatoblasts. Synthesis and secretion of albumin and AFP were already detected in the low numbered ventral foregut endodermal cells; fibrinogen synthesis was detectable in the E12 hepatoblasts, which were in higher number. The whole secretory machinery was functional from the earliest stages of liver development, and the speed of secretion was comparable with that of the adult hepatocytes. There was almost 4-fold increase of hepatoblasts cell volume in fetal stage compared with embryonic stage. The model used suggests that the hepatocyte secretory apparatus is already functional before the emergence of the liver bud. This is the first comparative report to analyze the hepatocyte secretory function, cell proliferation and cell volume during liver development.


Secretory apparatus Albumin Differentiation Cell volume Proprotein convertases Subtilisin-like proteinases 


  1. Abelev GI (1974) Alpha-fetoprotein as a marker of embryo-specific differentiations in normal and tumor tissues. Transplant Rev 20:3–37PubMedGoogle Scholar
  2. Belo JA, Bachiller D, Agius E, Kemp C, Borges AC, Marques S, Piccolo S, De Robertis EM (2000) Cerberus-like is a secreted BMP and nodal antagonist not essential for mouse development. Genesis 26:265–270PubMedCrossRefGoogle Scholar
  3. Bloom GS, Brashear TA (1989) A novel 58-kDa protein associates with the Golgi apparatus and microtubules. J Biol Chem 264:16083–16092PubMedGoogle Scholar
  4. Bossard P, Zaret KS (1998) GATA transcription factors as potentiators of gut endoderm differentiation. Development 125:4909–4917PubMedGoogle Scholar
  5. Burke Z, Oliver G (2002) Prox1 is an early specific marker for the developing liver and pancreas in the mammalian foregut endoderm. Mech Dev 118:147–155PubMedCrossRefGoogle Scholar
  6. Chirgwin JM, Przybyla AE, MacDonald RJ, Rutter WJ (1979) Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry 18:5294–5299PubMedCrossRefGoogle Scholar
  7. Duncan SA, Manova K, Chen WS, Hoodless P, Weinstein DC, Bachvarova RF, Darnell JE (1994) Expression of transcription factor HNF-4 in the extraembryonic endoderm, gut, and nephrogenic tissue of the developing mouse embryo: HNF-4 is a marker for primary endoderm in the implanting blastocyst. Proc Natl Acad Sci USA 91:7598–7602PubMedCrossRefGoogle Scholar
  8. Gitlin D (1973) Ontogeny of fetal plasma proteins. Tumor Res 8:1–6PubMedGoogle Scholar
  9. Greengard O, Federman M, Knox WE (1972) Cytomorphometry of developing rat liver and its application to enzymic differentiation. J Cell Biol 52:261–272PubMedCrossRefGoogle Scholar
  10. Gualdi R, Bossard P, Zheng M, Hamada Y, Coleman JR, Zaret KS (1996) Hepatic specification of the gut endoderm in vitro: cell signaling and transcriptional control. Genes Dev 10:1670–1682PubMedCrossRefGoogle Scholar
  11. Jung J, Zheng M, Goldfarb M, Zaret KS (1999) Initiation of mammalian liver development from endoderm by fibroblast growth factors. Science 284:1998–2003PubMedCrossRefGoogle Scholar
  12. Laemmli UK (1970) Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 227:680–685PubMedCrossRefGoogle Scholar
  13. Liao WS, Conn AR, Taylor JM (1980) Changes in rat alpha 1-fetoprotein and albumin mRNA levels during fetal and neonatal development. J Biol Chem 255:10036–10039PubMedGoogle Scholar
  14. Micsenyi A, Tan X, Sneddon T, Luo JH, Michalopoulos GK, Monga SP (2004) Beta-catenin is temporally regulated during normal liver development. Gastroenterology 126:1134–1146PubMedCrossRefGoogle Scholar
  15. Molkentin JD, Lin Q, Duncan SA, Olson EN (1997) Requirement of the transcription factor GATA4 for heart tube formation and ventral morphogenesis. Genes Dev 11:1061–1072PubMedCrossRefGoogle Scholar
  16. Mori K, Imamaki A, Nagata K, Yonetomi Y, Kiyokage-Yoshimoto R, Martin TJ, Gillespie MT, Nagahama M, Tsuji A, Matsuda Y (1999) Subtilisin-like proprotein convertases, PACE4 and PC8, as well as furin, are endogenous proalbumin convertases in HepG2 cells. J Biochem 125:627–633PubMedGoogle Scholar
  17. Muglia L, Locker J (1984) Developmental regulation of albumin and alpha-fetoprotein gene expression in the rat. Nucleic Acids Res 12:6751–6762CrossRefGoogle Scholar
  18. Narita N, Bielinska M, Wilson DB (1997) Wild-type endoderm abrogates the ventral developmental defects associated with GATA-4 deficiency in the mouse. Dev Biol 189:270–274PubMedCrossRefGoogle Scholar
  19. Neubauer K, Knittel T, Aurisch S, Fellmer P, Ramadori G (1996) Glial fibrillary acidic protein–a cell type specific marker for Ito cells in vivo and in vitro. J Hepatol 24:719–730PubMedCrossRefGoogle Scholar
  20. Petkov PM, Zavadil J, Goetz D, Chu T, Carver R, Rogler CE, Bottinger EP, Shafritz DA, Dabeva MD (2004) Gene expression pattern in hepatic stem/progenitor cells during rat fetal development using complementary DNA microarrays. Hepatology 39:617–627PubMedCrossRefGoogle Scholar
  21. Pringle NP, Yu WP, Howell M, Colvin JS, Ornitz DM, Richardson WD (2003) Fgfr3 expression by astrocytes and their precursors: evidence that astrocytes and oligodendrocytes originate in distinct neuroepithelial domains. Development 130:93–102PubMedCrossRefGoogle Scholar
  22. Ramadori G, Sipe JD, Dinarello CA, Mizel SB, Colten HR (1985) Pretranslational modulation of acute phase hepatic protein synthesis by murine recombinant interleukin 1 (IL-1) and purified human IL-1. J Exp Med 162:930–942PubMedCrossRefGoogle Scholar
  23. Ramadori G, Meyer zum Buschenfelde KH, Tobias PS, Mathison JC, Ulevitch RJ (1990) Biosynthesis of lipopolysaccharide-binding protein in rabbit hepatocytes. Pathobiology 58:89–94PubMedCrossRefGoogle Scholar
  24. Roebroek AJ, Taylor NA, Louagie E, Pauli I, Smeijers L, Snellinx A, Lauwers A, Van de Ven WJ, Hartmann D, Creemers JW (2004) Limited redundancy of the proprotein convertase furin in mouse liver. J Biol Chem 279:53442–53450PubMedCrossRefGoogle Scholar
  25. Rossi JM, Dunn NR, Hogan BL, Zaret KS (2001) Distinct mesodermal signals, including BMPs from the septum transversum mesenchyme, are required in combination for hepatogenesis from the endoderm. Genes Dev 15:1998–2009PubMedCrossRefGoogle Scholar
  26. Ruoslahti E, Terry WD (1976) Alpha foetoprotein and serum albumin show sequence homology. Nature 260:804–805PubMedCrossRefGoogle Scholar
  27. Serls AE, Doherty S, Parvatiyar P, Wells JM, Deutsch GH (2005) Different thresholds of fibroblast growth factors pattern the ventral foregut into liver and lung. Development 132:35–47PubMedCrossRefGoogle Scholar
  28. Sheikh N, Tron K, Dudas J, Ramadori G (2006) Cytokine-induced neutrophil chemoattractant-1 is released by the noninjured liver in a rat acute-phase model. Lab Invest 8:800–814Google Scholar
  29. Shiojiri N, Lemire JM, Fausto N (1991) Cell lineages and oval cell progenitors in rat liver development. Cancer Res 51:2611–2620PubMedGoogle Scholar
  30. Tessari P (2003) Protein metabolism in liver cirrhosis: from albumin to muscle myofibrils. Curr Opin Clin Nutr Metab Care 6:79–85PubMedCrossRefGoogle Scholar
  31. Tian JM, Schibler U (1991) Tissue-specific expression of the gene encoding hepatocyte nuclear factor 1 may involve hepatocyte nuclear factor 4. Genes Dev 5:2225–2234PubMedCrossRefGoogle Scholar
  32. Tworkowski KA, Salghetti SE, Tansey WP (2002) Stable and unstable pools of Myc protein exist in human cells. Oncogene 21:8515–8520PubMedCrossRefGoogle Scholar
  33. Vassy J, Kraemer M, Chalumeau MT, Foucrier J (1988) Development of the fetal rat liver: ultrastructural and stereological study of hepatocytes Cell Differ 24:9–24PubMedCrossRefGoogle Scholar
  34. Wilkinson DG, Nieto MA (1993) Detection of messenger RNA by in situ hybridization to tissue sections and whole mounts. Methods Enzymol 225:361–373PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Abderrahim Elmaouhoub
    • 1
  • József Dudas
    • 1
  • Giuliano Ramadori
    • 1
    • 2
    Email author
  1. 1.Department of Internal Medicine, Section of Gastroenterology and EndocrinologyGeorg-August-UniversityGoettingenGermany
  2. 2.Department of Gastroenterology and EndocrinologyGeorg-August-UniversityGoettingenGermany

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