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Development pp 479–498Cite as

Hepatocyte Differentiation

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Abstract

Despite a somewhat debatable taste and a rather mundane appearance, the liver is unquestionably essential to life. Indeed, among other tasks, the liver secretes plasma proteins, clotting factors and bile, detoxifies drugs and harmful by-products of cellular metabolism, and through gluconeogenesis supplies the body with glucose in times of severe stress. Although performing these diverse functions, the adult liver is predominantly composed of a single cell type — the hepatocyte — allowing the abstract and rather intimidating developmental question of “how does the liver form” to be roughly simplified to “how do hepatocytes form”. In this chapter, we will address the question of hepatocyte differentiation with specific reference to how hepatocytes acquire the specialized proteins, often unique to the liver, that enable these individual cells to perform the many tasks attributed to the liver as an organ (Table 1).

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References

  1. Hogan B, Constantini F, Lacy E (1986) Manipulating the mouse embryo. Cold Spring Harbor Laboratory Press, New York, pp 19–70.

    Google Scholar 

  2. Greengard O, Federman M, Knox WE (1972) Cytophotometry of developing rat liver and its application to enzymic differentiation. J Cell Biol 52:261–262.

    Article  PubMed  CAS  Google Scholar 

  3. Houssaint E (1980) Differentiation of the mouse hepatic primordium. I. An analysis of tissue interactions in hepatocyte development. Cell Differ 9:269–279.

    Article  PubMed  CAS  Google Scholar 

  4. Le Dourain NM (1975) An experimental analysis of liver development. Med Biol 53:427–455.

    Google Scholar 

  5. Shiojiri N (1981) Enzymo-and immunocytochemical analyses of the differentiation of liver cells in the prenatal mouse. J Embryol Exp Morphol 62:139–152.

    PubMed  CAS  Google Scholar 

  6. Bienz M, Tremml G (1988) Domain of ultrabithorax expression in Drosophila visceral mesoderm from autoregulation and exclusion. Nature 333:576–578.

    Article  PubMed  CAS  Google Scholar 

  7. Davis RL, Weintraub H, Lassar AB (1987) Expression of a single transfected cDNA converts fibroblasts to myoblasts. Cell 51:987–1000.

    Article  PubMed  CAS  Google Scholar 

  8. Gehring WJ (1987) Homeoboxes in the study of development. Science 236:1245–1252.

    Article  PubMed  CAS  Google Scholar 

  9. Hiromi Y, Gehring WJ (1987) Regulation and function of the Drosophila segmentation gene fushi tarazu. Cell 50:963–974.

    Article  PubMed  CAS  Google Scholar 

  10. Scott MP, Tamkun JW, Hartzell GW III (1989) The structure and function of the homeodomain. BBA Rev Cancer 989:25–49.

    CAS  Google Scholar 

  11. Weintraub H, Davis R, Tapscott S, Thayer M, Krause M, Benezra R, Blackwell TK, Turner D, Rupp R, Hollenberg S, Zhuang Y, Lassar A (1991) The myoD gene family: nodal point during specification of the muscle cell lineage. Science 251:761–766.

    Article  PubMed  CAS  Google Scholar 

  12. Wright WE, Sassoon DA, Lin VK (1989) Myogenin, a factor regulating myogenesis, has a domain homologous to MyoD. Cell 56:607–617.

    Article  PubMed  CAS  Google Scholar 

  13. Courtois G, Morgan JG, Campbell LA, Fourel G, Crabtree GR (1987) Interaction of a liver-specific factor with the fibrinogen and α-1-antitrypsin promoters. Science 238:688–692.

    Article  PubMed  CAS  Google Scholar 

  14. Courtois G, Baumheuter S, Crabtree GR (1988) Purified hepatocyte nuclear factor 1 interacts with a family of liverspecific promoters. Proc Natl Acad Sci USA 85:7937–7941.

    Article  PubMed  CAS  Google Scholar 

  15. Baumheuter S, Courtois G, Crabtree GR (1989) The role of HNF-1 in liver-specific gene expression. Ann N Y Acad Sci 69:272–279.

    Google Scholar 

  16. Baumheuter S, Mendel DB, Conley PB, Kuo CJ, Turk C, Graves MK, Edwards CA, Courtois G, Crabtree GR (1990) HNF-1 shares three sequence motifs with the POU domain proteins and is identical to LF-B1 and APR Genes Dev 4:372–379.

    Article  Google Scholar 

  17. Frain M, Swart G, Monaci P, Nicosia A, Stampfli S, Frank R, Cortese R (1989) The liver-specific transcription factor LF-B1 contains a highly diverged homeobox DNA-binding domain. Cell 59:145–157.

    Article  PubMed  CAS  Google Scholar 

  18. Kuo CJ, Conley PB, Hsieh C-L, Francke U, Crabtree GR (1990) Molecular cloning, functional expression and chromosomal localization of mouse hepatocyte nuclear factor 1. Proc Natl Acad Sci USA 87:9838–9842.

    Article  PubMed  CAS  Google Scholar 

  19. Lichtsteiner S, Schibier U (1989) A glycosylated liver-specific transcription factor stimulates transcription of the albumin gene. Cell 57:1179–1187.

    Article  PubMed  CAS  Google Scholar 

  20. Kuo CJ, Conley PB, Chen L, Sladek F, Darnell J, Crabtree GR (1992) A transcriptional hierarchy involved in mammalian cell-type specification. Nature 355:457–461.

    Article  PubMed  CAS  Google Scholar 

  21. Nicosia A, Monaci P, Tomei L, De Francesco R, Nuzzo M, Stunnenberg H, Cortese R (1990) A myosin-like dimerization helix and an extra-large homeodomain are essential elements of the tripartite DNA binding structure of LF-Bl. Cell 61:1225–1236.

    Article  PubMed  CAS  Google Scholar 

  22. Baumheuter S, Courtois G, Crabtree GR (1988) A variant nuclear protein in dedifferentiated hepatoma cells binds to the same functional sequences in the β-fibrinogen gene promoter as HNF-1. EMBO J 7:2485–2493.

    Google Scholar 

  23. Cereghini S, Blumenfeld M, Yaniv M (1988) A liver-specific factor essential for albumin transcription differs between differentiated and dedifferentiated rat hepatoma cells. Genes Dev2:957–974.

    Article  PubMed  CAS  Google Scholar 

  24. Deschatrette J, Weiss M (1974) Characterization of differentiated and dedifferentiated clones of a rat hepatoma. Biochimie 56:1603–1611.

    Article  PubMed  CAS  Google Scholar 

  25. Deschatrette J, Moore EE, Dubois M, Weiss M (1980) Dedifferentiated variants of a rat hepatoma: reversion analysis. Cell 19:1043–1051.

    Article  PubMed  CAS  Google Scholar 

  26. DeSimone V, De Magistris LD, Lazzaro D, Gertsner J, Monaci P, Nicosia A, Cortese R (1991) LFB3, a heterodimerforming homeoprotein of the LFB1 family, is expressed in specialized epithelia. EMBO J 10:1435–1443.

    CAS  Google Scholar 

  27. Kuo CJ, Mendel DB, Hansen LP, Crabtree GR (1991) Independent regulation of HNF-1α and HNF-1β by retinoic acid in F9 teratocarcinoma cells. EMBO J 10:2231–2236.

    PubMed  CAS  Google Scholar 

  28. Kuo CJ, Caron J, Crabtree GR unpublished observations Mendel D, Hansen L, Graves M, Conley P, Crabtree GR (1991) HNF-1α and HNF-1β share dimerization and homeo domains, but not activation domains, and form heterodimers in vitro. Genes Dev 5:1042–1056.

    Article  Google Scholar 

  29. Rey-Campos J, Chouard T, Yaniv M, Cereghini S (1991) vHNF1 is a homeoprotein that activates transcription and forms heterodimers with HNF1. EMBO J 10:1445–1457.

    PubMed  CAS  Google Scholar 

  30. Birkenmeier EH, Gwynne B, Howard S, Jerry J, Gordon JI, Landschultz W, McKnight SL (1989) Tissue-specific expression, developmental regulation, and genetic mapping of the gene encoding CCAAT/enhancer binding protein. Genes Dev 3:1146–1156.

    Article  PubMed  CAS  Google Scholar 

  31. Costa RH, Grayson DR, Xanthopoulous KG, Darnell JE (1988) A liver-specific DNA-binding protein recognizes multiple nucleotide sites in the regulatory regions of transthyretin, α-1-antitrypsin, albumin and SV40 genes. Proc Natl Acad Sci USA 85:3840–3844.

    Article  PubMed  CAS  Google Scholar 

  32. Friedman AD, Landschultz WH, McKnight SL (1989) CCAAT/Enhancer binding protein activates the promoter of the serum albumin gene in cultured hepatoma cells. Genes Dev 3:1314–1322.

    Article  PubMed  CAS  Google Scholar 

  33. Johnson PF, Landschultz WH, Graves BJ, McKnight SL (1987) Idenification of a rat liver nuclear protein that binds to the enhancer core of three animal viruses. Genes Dev 1:133–146.

    Article  PubMed  CAS  Google Scholar 

  34. Landschultz WH, Johnson PF, Adashi EY, Graves BJ, McKnight SL (1988) Isolation of a recombinant copy of the gene encoding C/EBP. Genes Dev 2:786–800.

    Article  Google Scholar 

  35. Landschultz WH, Johnson PF, McKnight SL (1988) The leucine zipper: a hypothetical structure common to a new class of DNA-binding proteins. Science 240:1759–1764.

    Article  Google Scholar 

  36. Maire P, Wuarin J, Schibier U (1989) In vitro dissection of the albumin gene promoter reveals positive cis-acting elements for tissue-specific and ubiquitous transcription factors. Science 244:343–346.

    Article  PubMed  CAS  Google Scholar 

  37. Umek RM, Friedman AD, McKnight SL (1991) CCAAT-Enhancer binding protein: a component of a differentiation switch. Science 251:288–292.

    Article  PubMed  CAS  Google Scholar 

  38. Xanthopoulos KG, Mirkovitch J, Decker T, Kuo CF, Darnell JE (1989) Cell-specific transcriptional control of the mouse DNA-binding protein mC/EBP. Proc Natl Acad Sci USA 86:4117–4121.

    Article  PubMed  CAS  Google Scholar 

  39. Descombes P, Chojkier M, Lichtsteiner S, Falvey E, Schibler U (1990) LAP, a novel member of the C/EBP gene family, encodes a liver-enriched transcriptional activator protein. Genes Dev4:1541–1551.

    Article  PubMed  CAS  Google Scholar 

  40. Mueller CR, Maire P, Schibler U (1990) DBP, a liver-enriched transcriptional activator is expressed late in ontogeny and its tissue specificity is determined post-transcriptionally. Cell 61:279–291.

    Article  PubMed  CAS  Google Scholar 

  41. Wuarin J, Schibler U (1990) Expression of the liver-enriched transcriptional activator protein DBP follows a stringent circadian rhythm. Cell 63:1257–1266.

    Article  PubMed  CAS  Google Scholar 

  42. Costa RH, Grayson DR, Darnell JE (1989) Multiple hepatocyte-enriched nuclear factors function in the regulation of transthyretin and α-1-antitrypsin genes. Mol Cell Biol9:1415–1425.

    PubMed  CAS  Google Scholar 

  43. Grayson DR, Costa RH, Darnell JE (1989) Regulation of hepatocyte-specific gene expression. Ann N Y Acad Sci 557:243–256.

    Article  PubMed  CAS  Google Scholar 

  44. Lai E, Prezioso VR, Smith E, Litvin O, Costa R H, Darnell JE (1990) HNF-3A, a hepatocyte-enriched transcription factor of novel structure is regulated transcriptionally. Genes Dev4:1427–1436.

    Article  PubMed  CAS  Google Scholar 

  45. Lai E, Prezioso VR, Tao W, Chen WS, Darnell JE (1991) Hepatocyte nuclear factor 3α belongs to a gene family in mammals that is homologous to the Drosophila homeotic genefork head. Genes Dev 5:416–427.

    Article  PubMed  CAS  Google Scholar 

  46. Weigel D, Jackie H (1990) The fork head domain: a novel DNA binding motif of eukaryotic transcription factors? Cell 63:455–456.

    Article  PubMed  CAS  Google Scholar 

  47. Weigel D, Seifert E, Reuter D, Jackie H (1990) Regulatory elements controlling expression of the Drosophila homeotic gene fork head. EMBO J 9:1199–1207.

    PubMed  CAS  Google Scholar 

  48. Kuo CJ, Conley PB, Chen L, Sladek F, Darnell J, Crabtree GR (1992) A transcriptional hierarchy involved in mammalian cell-type specification. Nature 355:457–461.

    Article  PubMed  CAS  Google Scholar 

  49. Sladek FM, Zhong W, Lai E, Darnell JE (1990) Liver-enriched transcription factor HNF-4 is a novel member of the steroid hormone receptor superfamily. Genes Dev 4:2353–2365.

    Article  PubMed  CAS  Google Scholar 

  50. Lichtsteiner S, Wuarin J, Schibler U (1987) The interplay of DNA-binding proteins on the promoter of the mouse albumin gene. Cell 51:963–973.

    Article  PubMed  CAS  Google Scholar 

  51. Maire P, Wuarin J, Schibler U (1989) In vitro dissection of the albumin gene promoter reveals positive cis-acting elements for tissue-specific and ubiquitous transcription factors. Science 244:343–346.

    Article  PubMed  CAS  Google Scholar 

  52. Lichtsteiner S, Schibler U (1989) A glycosylated liver-specific transcription factor stimulates transcription of the albumin gene. Cell 57:1179–1187.

    Article  PubMed  CAS  Google Scholar 

  53. Mendel DB, Crabtree GR unpublished observations.

    Google Scholar 

  54. Enat R, Reid LM (1984) Hepatocyte proliferation in vitro: its dependence on the use of serum-free hormonally defined medium and substrata of extracellular matrix. Proc Natl Acad Sci USA 81:1411–1415.

    Article  PubMed  CAS  Google Scholar 

  55. Jefferson DM, Clayton DF, Darnell JE Jr, Reid LM (1984) Post-transcriptional modulation of gene expression in cultured rat hepatocytes. Mol Cell Biol 4:1929–1934.

    PubMed  CAS  Google Scholar 

  56. Beato M (1989) Gene regulation by steroid hormones. Cell 56:335–344.

    Article  PubMed  CAS  Google Scholar 

  57. Granner DK, Hargrove JL (1983) Regulation of the synthesis of tyrosine aminotransferase: the relationship to mRNATAT. Mol Cell Biochem 53:113–128.

    Article  PubMed  Google Scholar 

  58. Yamamoto KR (1985) Steroid receptor regulated transcription of specific genes and gene networks. Annu Rev Genet 12:209–252.

    Article  Google Scholar 

  59. Castell JV, Andus T, Kunz D, Heinrich PC (1989) Interleukin 6: the major regulator of acute-phase protein synthesis in man and rat. Ann NY Acad Sci 557:87–101.

    Article  PubMed  CAS  Google Scholar 

  60. Evans E, Courtois G, Killiasn PL, Fuller GM, Crabtree GR (1987) Induction of fibrinogen and a subset of acute phase response genes involves a novel monokine which is mimicked by phorbol esters. J Biol Chem 262:10850–10854.

    PubMed  CAS  Google Scholar 

  61. Fey G (1989) Regulation of rat liver acute phase genes by interleukin-6 and production of hepatocyte stimulating factors by rat hepatoma cells. Ann NY Acad Sci 557:317–331.

    Article  PubMed  CAS  Google Scholar 

  62. Fowlkes DM, Mullis NT, Comeau CM, Crabtree GR (1984) Potential basis for regulation of the coordinately expressed fibrinogen genes: homology in the 5′ flanking regions. Proc Natl Acad Sci USA 81:2313–2316.

    Article  PubMed  CAS  Google Scholar 

  63. Poli V, Mancini FP, Cortese R (1990) IL-6DBP, a nuclear protein involved in interleukin-6 signal transduction, defines a new family of leucine zipper proteins related to C/EBP. Cell63:643–653.

    Article  PubMed  CAS  Google Scholar 

  64. Ben-Ze’ev A, Robinson GS, Bucher NR, Farmer SR (1988) Cell-cell and cell-matrix interactions differentially regulate the expression of hepatic and cytoskeletal genes in primary cultures of rat hepatocytes. Proc Natl Acad Sci USA 85:2161–2165.

    Article  CAS  Google Scholar 

  65. Clayton DF, Harrelson AL, Darnell JE Jr (1985) Dependence of liver-specific transcription on tissue organization. Mol Cell Biol 5:2623–2632.

    PubMed  CAS  Google Scholar 

  66. Guguen-Guillouzo C, Clement B, Baffet G, Beaumont C, Morel-Chany E, Glaise D, Guillouzo A (1983) Maintenance and reversibility of active albumin secretion by adult rat hepatocytes co-cultured with another liver epithelial cell type. Exp Cell Res 143:47–54.

    Article  PubMed  CAS  Google Scholar 

  67. Reinke R, Zipursky SL (1988) Cell-cell interaction in the Drosophila retina: the bride of sevenless gene is required in photoreceptor cell R8 for R7 cell development. Cell 55:321–330.

    Article  PubMed  CAS  Google Scholar 

  68. Rubin GM (1989) Development of the Drosophila retina: inductive events studied at single cell resolution. Cell 57:519–520.

    Article  PubMed  CAS  Google Scholar 

  69. Sorkin BC, Hemperly JJ, Edelman GM, Cunningham BA (1988) Structure of the gene for the liver cell adhesion molecule, L-CAM. Proc Natl Acad Sci USA 85:7617–7621.

    Article  PubMed  CAS  Google Scholar 

  70. Bissel DM, Arenson DM, Maher JJ, Roll FJ (1987) Support of cultured hepatocytes by a laminin-rich gel. J Clin Invest 79:801–812.

    Article  Google Scholar 

  71. Caron JM (1990) Induction of albumin gene transcription in hepatocytes by extracellular matrix proteins. Mol Cell Biol 10:1239–1243.

    PubMed  CAS  Google Scholar 

  72. Michealopoulos G, Pitot HC (1975) Primary culture of parenchymal liver cells on collagen membranes. Exp Cell Res 94:70–78.

    Article  Google Scholar 

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Authors
  1. Calvin J. Kuo
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  2. Gerald R. Grabtree
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© 1992 Springer-Verlag Berlin Heidelberg

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Kuo, C.J., Grabtree, G.R. (1992). Hepatocyte Differentiation. In: Development. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-77043-2_33

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  • DOI: https://doi.org/10.1007/978-3-642-77043-2_33

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-642-77045-6

  • Online ISBN: 978-3-642-77043-2

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