Transcriptional Control of Hepatocyte Differentiation

Part of the Molecular Pathology Library book series (MPLB, volume 5)


The unique gene expression that defines the hepatocyte conforms to a set of general regulatory principles. The genome encodes the programs of mature gene expression and of the preceding developmental stages. Transcription factors execute these programs by binding to specific DNA sequence motifs grouped together as promoters and enhancers. Expression of each gene therefore reflects the synergistic integration of separate regulations via individual factors. Each cell type expresses a distinctive mixture of hundreds of transcription factors. This mixture, superimposed on the epigenetic history of the cell, determines its phenotype.


Bile Acid Nuclear Receptor Constitutive Androstane Receptor Mature Liver C2H2 Zinc Finger 
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.


  1. 1.
    Courtois G, Morgan JG, Campbell LA, Fourel G, Crabtree GR. Interaction of a liver-specific nuclear factor with the fibrinogen and alpha 1-antitrypsin promoters. Science. 1987;238:688–92.PubMedGoogle Scholar
  2. 2.
    Johnson PF, Landschulz WH, Graves BJ, McKnight SL. Identification of a rat liver nuclear protein that binds to the enhancer core element of three animal viruses. Genes Dev. 1987;1:133–46.PubMedGoogle Scholar
  3. 3.
    Cereghini S, Blumenfeld M, Yaniv M. A liver-specific factor essential for albumin transcription differs between differentiated and dedifferentiated rat hepatoma cells. Genes Dev. 1988;2:957–74.PubMedGoogle Scholar
  4. 4.
    Costa RH, Grayson DR, Darnell Jr JE. Multiple hepatocyte-enriched nuclear factors function in the regulation of transthyretin and alpha 1-antitrypsin genes. Mol Cell Biol. 1989;9:1415–25.PubMedGoogle Scholar
  5. 5.
    Sladek FM, Zhong WM, Lai E, Darnell Jr JE. Liver-enriched transcription factor HNF-4 is a novel member of the steroid hormone receptor superfamily. Genes Dev. 1990;4:2353–65.PubMedGoogle Scholar
  6. 6.
    Lemaigre FP, Durviaux SM, Truong O, Lannoy VJ, Hsuan JJ, Rousseau GG. Hepatocyte nuclear factor 6, a transcription factor that contains a novel type of homeodomain and a single cut domain. Proc Natl Acad Sci U S A. 1996;93:9460–4.PubMedGoogle Scholar
  7. 7.
    Samadani U, Costa RH. The transcriptional activator hepatocyte nuclear factor 6 regulates liver gene expression. Mol Cell Biol. 1996;16:6273–84.PubMedGoogle Scholar
  8. 8.
    Tian JM, Schibler U. Tissue-specific expression of the gene encoding hepatocyte nuclear factor 1 may involve hepatocyte nuclear factor 4. Genes Dev. 1991;5:2225–34.PubMedGoogle Scholar
  9. 9.
    Kyrmizi I, Hatzis P, Katrakili N, Tronche F, Gonzalez FJ, Talianidis I. Plasticity and expanding complexity of the hepatic transcription factor network during liver development. Genes Dev. 2006;20:2293–305.PubMedGoogle Scholar
  10. 10.
    Odom DT, Dowell RD, Jacobsen ES, et al. Core transcriptional regulatory circuitry in human hepatocytes. Mol Syst Biol. 2006;2:2006.0017.PubMedGoogle Scholar
  11. 11.
    Jiang J, Levine M. Binding affinities and cooperative interactions with bHLH activators delimit threshold responses to the dorsal gradient morphogen. Cell. 1993;72:741–52.PubMedGoogle Scholar
  12. 12.
    Panne D, Maniatis T, Harrison SC. An atomic model of the interferon-beta enhanceosome. Cell. 2007;129:1111–23.PubMedGoogle Scholar
  13. 13.
    Vorachek WR, Steppan CM, Lima M, et al. Distant enhancers stimulate the albumin promoter through complex proximal binding sites. J Biol Chem. 2000;275:29031–41.PubMedGoogle Scholar
  14. 14.
    Chaya D, Hayamizu T, Bustin M, Zaret KS. Transcription factor FoxA (HNF3) on a nucleosome at an enhancer complex in liver chromatin. J Biol Chem. 2001;276:44385–9.PubMedGoogle Scholar
  15. 15.
    Kajiyama Y, Tian J, Locker J. Characterization of distant enhancers and promoters in the albumin-alpha-fetoprotein locus during active and silenced expression. J Biol Chem. 2006;281:30122–31.PubMedGoogle Scholar
  16. 16.
    Costa RH, Kalinichenko VV, Holterman AX, Wang X. Transcription factors in liver development, differentiation, and regeneration. Hepatology. 2003;38:1331–47.PubMedGoogle Scholar
  17. 17.
    Hatzis P, Talianidis I. Dynamics of enhancer-promoter communication during differentiation-induced gene activation. Mol Cell. 2002;10:1467–77.PubMedGoogle Scholar
  18. 18.
    Yang J, Reshef L, Cassuto H, Aleman G, Hanson RW. Aspects of the control of phosphoenolpyruvate carboxykinase gene transcription. J Biol Chem. 2009;284:27031–5.PubMedGoogle Scholar
  19. 19.
    Motallebipour M, Ameur A. Reddy Bysani MS, et al. Differential binding and co-binding pattern of FOXA1 and FOXA3 and their relation to H3K4me3 in HepG2 cells revealed by ChIP-seq. Genome Biol. 2009;10:R129.PubMedGoogle Scholar
  20. 20.
    Tuteja G, White P, Schug J, Kaestner KH. Extracting transcription factor targets from ChIP-Seq data. Nucleic Acids Res. 2009;37:e113.PubMedGoogle Scholar
  21. 21.
    Le Lay J, Kaestner KH. The Fox genes in the liver: from organogenesis to functional integration. Physiol Rev. 2010;90:1–22.PubMedGoogle Scholar
  22. 22.
    Friedman JR, Kaestner KH. The Foxa family of transcription factors in development and metabolism. Cell Mol Life Sci. 2006;63:2317–28.PubMedGoogle Scholar
  23. 23.
    Zaret KS, Watts J, Xu J, Wandzioch E, Smale ST, Sekiya T. Pioneer factors, genetic competence, and inductive signaling: programming liver and pancreas progenitors from the endoderm. Cold Spring Harb Symp Quant Biol. 2008;73:119–26.PubMedGoogle Scholar
  24. 24.
    Xu J, Watts JA, Pope SD, et al. Transcriptional competence and the active marking of tissue-specific enhancers by defined transcription factors in embryonic and induced pluripotent stem cells. Genes Dev. 2009;23:2824–38.PubMedGoogle Scholar
  25. 25.
    Keng VW, Yagi H, Ikawa M, et al. Homeobox gene Hex is essential for onset of mouse embryonic liver development and differentiation of the monocyte lineage. Biochem Biophys Res Commun. 2000;276:1155–61.PubMedGoogle Scholar
  26. 26.
    Hunter MP, Wilson CM, Jiang X, et al. The homeobox gene Hhex is essential for proper hepatoblast differentiation and bile duct morphogenesis. Dev Biol. 2007;308:355–67.PubMedGoogle Scholar
  27. 27.
    Denson LA, Karpen SJ, Bogue CW, Jacobs HC. Divergent homeobox gene hex regulates promoter of the Na(+)-dependent bile acid cotransporter. Am J Physiol Gastrointest Liver Physiol. 2000;279:G347–55.PubMedGoogle Scholar
  28. 28.
    Tanaka H, Yamamoto T, Ban T, et al. Hex stimulates the hepatocyte nuclear factor 1alpha-mediated activation of transcription. Arch Biochem Biophys. 2005;442:117–24.PubMedGoogle Scholar
  29. 29.
    Desjobert C, Noy P, Swingler T, Williams H, Gaston K, Jayaraman PS. The PRH/Hex repressor protein causes nuclear retention of Groucho/TLE co-repressors. Biochem J. 2009;417:121–32.PubMedGoogle Scholar
  30. 30.
    Soufi A, Jayaraman PS. PRH/Hex: an oligomeric transcription factor and multifunctional regulator of cell fate. Biochem J. 2008;412:399–413.PubMedGoogle Scholar
  31. 31.
    Zhao R, Watt AJ, Li J, Luebke-Wheeler J, Morrisey EE, Duncan SA. GATA6 is essential for embryonic development of the liver but dispensable for early heart formation. Mol Cell Biol. 2005;25:2622–31.PubMedGoogle Scholar
  32. 32.
    Denson LA, McClure MH, Bogue CW, Karpen SJ, Jacobs HC. HNF3beta and GATA-4 transactivate the liver-enriched homeobox gene, Hex. Gene. 2000;246:311–20.PubMedGoogle Scholar
  33. 33.
    Morrisey EE, Tang Z, Sigrist K, et al. GATA6 regulates HNF4 and is required for differentiation of visceral endoderm in the mouse embryo. Genes Dev. 1998;12:3579–90.PubMedGoogle Scholar
  34. 34.
    Divine JK, Staloch LJ, Haveri H, et al. GATA-4, GATA-5, and GATA-6 activate the rat liver fatty acid binding protein gene in concert with HNF-1alpha. Am J Physiol Gastrointest Liver Physiol. 2004;287:G1086–99.PubMedGoogle Scholar
  35. 35.
    Zaret KS, Grompe M. Generation and regeneration of cells of the liver and pancreas. Science. 2008;322:1490–4.PubMedGoogle Scholar
  36. 36.
    Ludtke TH, Christoffels VM, Petry M, Kispert A. Tbx3 promotes liver bud expansion during mouse development by suppression of cholangiocyte differentiation. Hepatology. 2009;49:969–78.PubMedGoogle Scholar
  37. 37.
    Margagliotti S, Clotman F, Pierreux CE, et al. The Onecut transcription factors HNF-6/OC-1 and OC-2 regulate early liver expansion by controlling hepatoblast migration. Dev Biol. 2007;311:579–89.PubMedGoogle Scholar
  38. 38.
    Parviz F, Matullo C, Garrison WD, et al. Hepatocyte nuclear factor 4alpha controls the development of a hepatic epithelium and liver morphogenesis. Nat Genet. 2003;34:292–6.PubMedGoogle Scholar
  39. 39.
    Lokmane L, Haumaitre C, Garcia-Villalba P, Anselme I, Schneider-Maunoury S, Cereghini S. Crucial role of vHNF1 in vertebrate hepatic specification. Development. 2008;135:2777–86.PubMedGoogle Scholar
  40. 40.
    Suzuki A, Sekiya S, Buscher D, Izpisua Belmonte JC, Taniguchi H. Tbx3 controls the fate of hepatic progenitor cells in liver development by suppressing p19ARF expression. Development. 2008;135:1589–95.PubMedGoogle Scholar
  41. 41.
    Renard CA, Labalette C, Armengol C, et al. Tbx3 is a downstream target of the Wnt/beta-catenin pathway and a critical mediator of beta-catenin survival functions in liver cancer. Cancer Res. 2007;67:901–10.PubMedGoogle Scholar
  42. 42.
    Kamiya A, Kakinuma S, Onodera M, Miyajima A, Nakauchi H. Prospero-related homeobox 1 and liver receptor homolog 1 coordinately regulate long-term proliferation of murine fetal hepatoblasts. Hepatology. 2008;48:252–64.PubMedGoogle Scholar
  43. 43.
    Sosa-Pineda B, Wigle JT, Oliver G. Hepatocyte migration during liver development requires Prox1. Nat Genet. 2000;25:254–5.PubMedGoogle Scholar
  44. 44.
    Dudas J, Elmaouhoub A, Mansuroglu T, et al. Prospero-related homeobox 1 (Prox1) is a stable hepatocyte marker during liver development, injury and regeneration, and is absent from “oval cells”. Histochem Cell Biol. 2006;126:549–62.PubMedGoogle Scholar
  45. 45.
    Qin J, Gao DM, Jiang QF, et al. Prospero-related homeobox (Prox1) is a corepressor of human liver receptor homolog-1 and suppresses the transcription of the cholesterol 7-alpha-hydroxylase gene. Mol Endocrinol. 2004;18:2424–39.PubMedGoogle Scholar
  46. 46.
    Jacquemin P, Lannoy VJ, Rousseau GG, Lemaigre FP. OC-2, a novel mammalian member of the ONECUT class of homeodomain transcription factors whose function in liver partially overlaps with that of hepatocyte nuclear factor-6. J Biol Chem. 1999;274:2665–71.PubMedGoogle Scholar
  47. 47.
    Odom DT, Zizlsperger N, Gordon DB, et al. Control of pancreas and liver gene expression by HNF transcription factors. Science. 2004;303:1378–81.PubMedGoogle Scholar
  48. 48.
    Clotman F, Lannoy VJ, Reber M, et al. The onecut transcription factor HNF6 is required for normal development of the biliary tract. Development. 2002;129:1819–28.PubMedGoogle Scholar
  49. 49.
    Bolotin E, Liao H, Ta TC, et al. Integrated approach for the identification of human hepatocyte nuclear factor 4alpha target genes using protein binding microarrays. Hepatology. 2010;51:642–53.PubMedGoogle Scholar
  50. 50.
    Yuan X, Ta TC, Lin M, et al. Identification of an endogenous ligand bound to a native orphan nuclear receptor. PLoS ONE. 2009;4:e5609.PubMedGoogle Scholar
  51. 51.
    Martinez-Jimenez CP, Kyrmizi I, Cardot P, Gonzalez FJ, Talianidis I. HNF4{alpha} coordinates a transcription factor network regulating hepatic fatty acid metabolism. Mol Cell Biol. 2010;30:565–77.PubMedGoogle Scholar
  52. 52.
    Stanulovic VS, Kyrmizi I, Kruithof-de Julio M, et al. Hepatic HNF4alpha deficiency induces periportal expression of glutamine synthetase and other pericentral enzymes. Hepatology. 2007;45:433–44.PubMedGoogle Scholar
  53. 53.
    Torre C, Perret C, Colnot S. Transcription dynamics in a physiological process: beta-catenin signaling directs liver metabolic zonation. Int J Biochem Cell Biol. in press.Google Scholar
  54. 54.
    Micsenyi A, Tan X, Sneddon T, Luo JH, Michalopoulos GK, Monga SP. Beta-catenin is temporally regulated during normal liver development. Gastroenterology. 2004;126:1134–46.PubMedGoogle Scholar
  55. 55.
    Arce L, Yokoyama NN, Waterman ML. Diversity of LEF/TCF action in development and disease. Oncogene. 2006;25:7492–504.PubMedGoogle Scholar
  56. 56.
    Colletti M, Cicchini C, Conigliaro A, et al. Convergence of Wnt signaling on the HNF4alpha-driven transcription in controlling liver zonation. Gastroenterology. 2009;137:660–72.PubMedGoogle Scholar
  57. 57.
    Monga SP, Monga HK, Tan X, Mule K, Pediaditakis P, Michalopoulos GK. Beta-catenin antisense studies in embryonic liver cultures: role in proliferation, apoptosis, and lineage specification. Gastroenterology. 2003;124:202–16.PubMedGoogle Scholar
  58. 58.
    Tan X, Yuan Y, Zeng G, et al. Beta-catenin deletion in hepatoblasts disrupts hepatic morphogenesis and survival during mouse development. Hepatology. 2008;47:1667–79.PubMedGoogle Scholar
  59. 59.
    Hussain SZ, Sneddon T, Tan X, Micsenyi A, Michalopoulos GK, Monga SP. Wnt impacts growth and differentiation in ex vivo liver development. Exp Cell Res. 2004;292:157–69.PubMedGoogle Scholar
  60. 60.
    Lichtsteiner S, Schibler U. A glycosylated liver-specific transcription factor stimulates transcription of the albumin gene. Cell. 1989;57:1179–87.PubMedGoogle Scholar
  61. 61.
    Tronche F, Yaniv M. HNF1, a homeoprotein member of the hepatic transcription regulatory network. BioEssays. 1992;14:579–87.PubMedGoogle Scholar
  62. 62.
    Locker J, Ghosh D, Luc PV, Zheng J. Definition and prediction of the full range of transcription factor binding sites – the hepatocyte nuclear factor 1 dimeric site. Nucleic Acids Res. 2002;30:3809–17.PubMedGoogle Scholar
  63. 63.
    Pontoglio M. Hepatocyte nuclear factor 1, a transcription factor at the crossroads of glucose homeostasis. J Am Soc Nephrol. 2000;11 Suppl 16:S140–3.PubMedGoogle Scholar
  64. 64.
    Pontoglio M, Barra J, Hadchouel M, et al. Hepatocyte nuclear factor 1 inactivation results in hepatic dysfunction, phenylketonuria, and renal Fanconi syndrome. Cell. 1996;84:575–85.PubMedGoogle Scholar
  65. 65.
    Hiroki T, Liebhaber SA, Cooke NE. An intronic locus control region plays an essential role in the establishment of an autonomous hepatic chromatin domain for the human vitamin D-binding protein gene. Mol Cell Biol. 2007;27:7365–80.PubMedGoogle Scholar
  66. 66.
    Westmacott A, Burke ZD, Oliver G, Slack JM, Tosh D. C/EBPalpha and C/EBPbeta are markers of early liver development. Int J Dev Biol. 2006;50:653–7.PubMedGoogle Scholar
  67. 67.
    Schrem H, Klempnauer J, Borlak J. Liver-enriched transcription factors in liver function and development. Part II: the C/EBPs and D site-binding protein in cell cycle control, carcinogenesis, circadian gene regulation, liver regeneration, apoptosis, and liver-specific gene regulation. Pharmacol Rev. 2004;56:291–330.PubMedGoogle Scholar
  68. 68.
    Friedman JR, Larris B, Le PP, et al. Orthogonal analysis of C/EBPbeta targets in vivo during liver proliferation. Proc Natl Acad Sci U S A. 2004;101:12986–91.PubMedGoogle Scholar
  69. 69.
    Falvey E, Marcacci L, Schibler U. DNA-binding specificity of PAR and C/EBP leucine zipper proteins: a single amino acid substitution in the C/EBP DNA-binding domain confers PAR-like specificity to C/EBP. Biol Chem. 1996;377:797–809.PubMedGoogle Scholar
  70. 70.
    Wang ND, Finegold MJ, Bradley A, et al. Impaired energy homeostasis in C/EBP alpha knockout mice. Science. 1995;269:1108–12.PubMedGoogle Scholar
  71. 71.
    Johnson PF. Molecular stop signs: regulation of cell-cycle arrest by C/EBP transcription factors. J Cell Sci. 2005;118:2545–55.PubMedGoogle Scholar
  72. 72.
    Lee AH, Glimcher LH. Intersection of the unfolded protein response and hepatic lipid metabolism. Cell Mol Life Sci. 2009;66:2835–50.PubMedGoogle Scholar
  73. 73.
    Yoshida H. Unconventional splicing of XBP-1 mRNA in the unfolded protein response. Antioxid Redox Signal. 2007;9:2323–33.PubMedGoogle Scholar
  74. 74.
    Hai T, Liu F, Allegretto EA, Karin M, Green MR. A family of immunologically related transcription factors that includes multiple forms of ATF and AP-1. Genes Dev. 1988;2:1216–26.PubMedGoogle Scholar
  75. 75.
    Shaulian E, Karin M. AP-1 as a regulator of cell life and death. Nat Cell Biol. 2002;4:E131–6.PubMedGoogle Scholar
  76. 76.
    Yang Y, Cvekl A. Large Maf transcription factors: cousins of AP-1 proteins and important regulators of cellular differentiation. Einstein J Biol Med. 2007;23:2–11.PubMedGoogle Scholar
  77. 77.
    Herzig S, Hedrick S, Morantte I, Koo SH, Galimi F, Montminy M. CREB controls hepatic lipid metabolism through nuclear hormone receptor PPAR-gamma. Nature. 2003;426:190–3.PubMedGoogle Scholar
  78. 78.
    Chakravarty K, Cassuto H, Reshef L, Hanson RW. Factors that control the tissue-specific transcription of the gene for phosphoenolpyruvate carboxykinase-C. Crit Rev Biochem Mol Biol. 2005;40:129–54.PubMedGoogle Scholar
  79. 79.
    Luebke-Wheeler J, Zhang K, Battle M, et al. Hepatocyte nuclear factor 4alpha is implicated in endoplasmic reticulum stress-induced acute phase response by regulating expression of cyclic adenosine monophosphate responsive element binding protein H. Hepatology. 2008;48:1242–50.PubMedGoogle Scholar
  80. 80.
    Shimizu YI, Morita M, Ohmi A, et al. Fasting induced up-regulation of activating transcription factor 5 in mouse liver. Life Sci. 2009;84:894–902.PubMedGoogle Scholar
  81. 81.
    Hai T, Curran T. Cross-family dimerization of transcription factors Fos/Jun and ATF/CREB alters DNA binding specificity. Proc Natl Acad Sci U S A. 1991;88:3720–4.PubMedGoogle Scholar
  82. 82.
    Jochum W, Passegue E, Wagner EF. AP-1 in mouse development and tumorigenesis. Oncogene. 2001;20:2401–12.PubMedGoogle Scholar
  83. 83.
    Zhou D, Palam LR, Jiang L, Narasimhan J, Staschke KA, Wek RC. Phosphorylation of eIF2 directs ATF5 translational control in response to diverse stress conditions. J Biol Chem. 2008;283:7064–73.PubMedGoogle Scholar
  84. 84.
    Hartman MG, Lu D, Kim ML, et al. Role for activating transcription factor 3 in stress-induced beta-cell apoptosis. Mol Cell Biol. 2004;24:5721–32.PubMedGoogle Scholar
  85. 85.
    Gray S, Feinberg MW, Hull S, et al. The Kruppel-like factor KLF15 regulates the insulin-sensitive glucose transporter GLUT4. J Biol Chem. 2002;277:34322–8.PubMedGoogle Scholar
  86. 86.
    Gray S, Wang B, Orihuela Y, et al. Regulation of gluconeogenesis by Kruppel-like factor 15. Cell Metab. 2007;5:305–12.PubMedGoogle Scholar
  87. 87.
    Horton JD, Goldstein JL, Brown MS. SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J Clin Invest. 2002;109:1125–31.PubMedGoogle Scholar
  88. 88.
    Bennett MK, Seo YK, Datta S, Shin DJ, Osborne TF. Selective binding of sterol regulatory element-binding protein isoforms and co-regulatory proteins to promoters for lipid metabolic genes in liver. J Biol Chem. 2008;283:15628–37.PubMedGoogle Scholar
  89. 89.
    Horton JD, Shah NA, Warrington JA, et al. Combined analysis of oligonucleotide microarray data from transgenic and knockout mice identifies direct SREBP target genes. Proc Natl Acad Sci U S A. 2003;100:12027–32.PubMedGoogle Scholar
  90. 90.
    Gachon F, Olela FF, Schaad O, Descombes P, Schibler U. The circadian PAR-domain basic leucine zipper transcription factors DBP, TEF, and HLF modulate basal and inducible xenobiotic detoxification. Cell Metab. 2006;4:25–36.PubMedGoogle Scholar
  91. 91.
    Mueller CR, Maire P, Schibler U. DBP, a liver-enriched transcriptional activator, is expressed late in ontogeny and its tissue specificity is determined posttranscriptionally. Cell. 1990;61:279–91.PubMedGoogle Scholar
  92. 92.
    Li T, Huang J, Jiang Y, et al. Multi-stage analysis of gene expression and transcription regulation in C57/B6 mouse liver development. Genomics. 2009;93:235–42.PubMedGoogle Scholar
  93. 93.
    Wuarin J, Falvey E, Lavery D, et al. The role of the transcriptional activator protein DBP in circadian liver gene expression. J Cell Sci Suppl. 1992;16:123–7.PubMedGoogle Scholar
  94. 94.
    Fonjallaz P, Ossipow V, Wanner G, Schibler U. The two PAR leucine zipper proteins, TEF and DBP, display similar circadian and tissue-specific expression, but have different target promoter preferences. Embo J. 1996;15:351–62.PubMedGoogle Scholar
  95. 95.
    Ripperger JA, Schibler U. Rhythmic CLOCK-BMAL1 binding to multiple E-box motifs drives circadian Dbp transcription and chromatin transitions. Nat Genet. 2006;38:369–74.PubMedGoogle Scholar
  96. 96.
    Xu CX, Krager SL, Liao DF, Tischkau SA. Disruption of clock/BMAL1 transcriptional activity is responsible for aryl hydrocarbon receptor-mediated regulation of period1 gene. Toxicol Sci. 2010;115:98–108.PubMedGoogle Scholar
  97. 97.
    Rigamonti E, Chinetti-Gbaguidi G, Staels B. Regulation of macrophage functions by PPAR-alpha, PPAR-gamma, and LXRs in mice and men. Arterioscler Thromb Vasc Biol. 2008;28:1050–9.PubMedGoogle Scholar
  98. 98.
    Chawla A, Boisvert WA, Lee CH, et al. A PPAR gamma-LXR-ABCA1 pathway in macrophages is involved in cholesterol efflux and atherogenesis. Mol Cell. 2001;7:161–71.PubMedGoogle Scholar
  99. 99.
    Jung D, Mangelsdorf DJ, Meyer UA. Pregnane X receptor is a target of farnesoid X receptor. J Biol Chem. 2006;281:19081–91.PubMedGoogle Scholar
  100. 100.
    Kajiyama Y, Tian J, Locker J. Regulation of alpha-fetoprotein expression by Nkx2.8. Mol Cell Biol. 2002;22:6122–30.PubMedGoogle Scholar
  101. 101.
    Lee YK, Schmidt DR, Cummins CL, et al. Liver receptor homolog-1 regulates bile acid homeostasis but is not essential for feedback regulation of bile acid synthesis. Mol Endocrinol. 2008;22:1345–56.PubMedGoogle Scholar
  102. 102.
    Galarneau L, Pare JF, Allard D, et al. The alpha1-fetoprotein locus is activated by a nuclear receptor of the Drosophila FTZ-F1 family. Mol Cell Biol. 1996;16:3853–65.PubMedGoogle Scholar
  103. 103.
    Krylova IN, Sablin EP, Moore J, et al. Structural analyses reveal phosphatidyl inositols as ligands for the NR5 orphan receptors SF-1 and LRH-1. Cell. 2005;120:343–55.PubMedGoogle Scholar
  104. 104.
    Ortlund EA, Lee Y, Solomon IH, et al. Modulation of human nuclear receptor LRH-1 activity by phospholipids and SHP. Nat Struct Mol Biol. 2005;12:357–63.PubMedGoogle Scholar
  105. 105.
    Steffensen KR, Holter E, Bavner A, et al. Functional conservation of interactions between a homeodomain cofactor and a mammalian FTZ-F1 homologue. EMBO Rep. 2004;5:613–9.PubMedGoogle Scholar
  106. 106.
    Warnecke M, Oster H, Revelli JP, Alvarez-Bolado G, Eichele G. Abnormal development of the locus coeruleus in Ear2(Nr2f6)-deficient mice impairs the functionality of the forebrain clock and affects nociception. Genes Dev. 2005;19:614–25.PubMedGoogle Scholar
  107. 107.
    Kruse SW, Suino-Powell K, Zhou XE, et al. Identification of COUP-TFII orphan nuclear receptor as a retinoic acid-activated receptor. PLoS Biol. 2008;6:e227.PubMedGoogle Scholar
  108. 108.
    Li L, Xie X, Qin J, et al. The nuclear orphan receptor COUP-TFII plays an essential role in adipogenesis, glucose homeostasis, and energy metabolism. Cell Metab. 2009;9:77–87.PubMedGoogle Scholar
  109. 109.
    Qiu Y, Pereira FA, DeMayo FJ, Lydon JP, Tsai SY, Tsai MJ. Null mutation of mCOUP-TFI results in defects in morphogenesis of the glossopharyngeal ganglion, axonal projection, and arborization. Genes Dev. 1997;11:1925–37.PubMedGoogle Scholar
  110. 110.
    Ktistaki E, Lacorte JM, Katrakili N, Zannis VI, Talianidis I. Transcriptional regulation of the apolipoprotein A-IV gene involves synergism between a proximal orphan receptor response element and a distant enhancer located in the upstream promoter region of the apolipoprotein C-III gene. Nucleic Acids Res. 1994;22:4689–96.PubMedGoogle Scholar
  111. 111.
    Bavner A, Sanyal S, Gustafsson JA, Treuter E. Transcriptional corepression by SHP: molecular mechanisms and physiological consequences. Trends Endocrinol Metab. 2005;16:478–88.PubMedGoogle Scholar
  112. 112.
    Li Y, Choi M, Suino K, et al. Structural and biochemical basis for selective repression of the orphan nuclear receptor liver receptor homolog 1 by small heterodimer partner. Proc Natl Acad Sci U S A. 2005;102:9505–10.PubMedGoogle Scholar
  113. 113.
    Claudel T, Cretenet G, Saumet A, Gachon F. Crosstalk between xenobiotics metabolism and circadian clock. FEBS Lett. 2007;581:3626–33.PubMedGoogle Scholar
  114. 114.
    Wang YD, Chen WD, Moore DD, Huang W. FXR: a metabolic regulator and cell protector. Cell Res. 2008;18:1087–95.PubMedGoogle Scholar
  115. 115.
    Sinal CJ, Tohkin M, Miyata M, Ward JM, Lambert G, Gonzalez FJ. Targeted disruption of the nuclear receptor FXR/BAR impairs bile acid and lipid homeostasis. Cell. 2000;102:731–44.PubMedGoogle Scholar
  116. 116.
    Moschetta A, Bookout AL, Mangelsdorf DJ. Prevention of cholesterol gallstone disease by FXR agonists in a mouse model. Nat Med. 2004;10:1352–8.PubMedGoogle Scholar
  117. 117.
    Thomas AM, Hart SN, Kong B, Fang J, Zhong XB, Guo GL. Genome-wide tissue-specific farnesoid X receptor binding in mouse liver and intestine. Hepatology. 2009;51:1410–9.Google Scholar
  118. 118.
    Goodwin B, Jones SA, Price RR, et al. A regulatory cascade of the nuclear receptors FXR, SHP-1, and LRH-1 represses bile acid biosynthesis. Mol Cell. 2000;6:517–26.PubMedGoogle Scholar
  119. 119.
    Kalaany NY, Gauthier KC, Zavacki AM, et al. LXRs regulate the balance between fat storage and oxidation. Cell Metab. 2005;1:231–44.PubMedGoogle Scholar
  120. 120.
    Li Y, Bolten C, Bhat BG, et al. Induction of human liver X receptor alpha gene expression via an autoregulatory loop mechanism. Mol Endocrinol. 2002;16:506–14.PubMedGoogle Scholar
  121. 121.
    Reddy JK. Peroxisome proliferators and peroxisome proliferator-activated receptor alpha: biotic and xenobiotic sensing. Am J Pathol. 2004;164:2305–21.PubMedGoogle Scholar
  122. 122.
    Xu HE, Li Y. Ligand-dependent and -independent regulation of PPAR gamma and orphan nuclear receptors. Sci Signal. 2008;1:pe52.PubMedGoogle Scholar
  123. 123.
    Yang Q, Nagano T, Shah Y, Cheung C, Ito S, Gonzalez FJ. The PPAR alpha-humanized mouse: a model to investigate species differences in liver toxicity mediated by PPAR alpha. Toxicol Sci. 2008;101:132–9.PubMedGoogle Scholar
  124. 124.
    DeLuca JG, Doebber TW, Kelly LJ, et al. Evidence for peroxisome proliferator-activated receptor (PPAR)alpha-independent peroxisome proliferation: effects of PPARgamma/delta-specific agonists in PPARalpha-null mice. Mol Pharmacol. 2000;58:470–6.PubMedGoogle Scholar
  125. 125.
    Chandra V, Huang P, Hamuro Y, et al. Structure of the intact PPAR-gamma-RXR-alpha nuclear receptor complex on DNA. Nature. 2008;456:350–6.PubMedGoogle Scholar
  126. 126.
    Lehmann JM, McKee DD, Watson MA, Willson TM, Moore JT, Kliewer SA. The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions. J Clin Invest. 1998;102:1016–23.PubMedGoogle Scholar
  127. 127.
    Staudinger JL, Goodwin B, Jones SA, et al. The nuclear receptor PXR is a lithocholic acid sensor that protects against liver toxicity. Proc Natl Acad Sci U S A. 2001;98:3369–74.PubMedGoogle Scholar
  128. 128.
    Xie W, Radominska-Pandya A, Shi Y, et al. An essential role for nuclear receptors SXR/PXR in detoxification of cholestatic bile acids. Proc Natl Acad Sci U S A. 2001;98:3375–80.PubMedGoogle Scholar
  129. 129.
    Vyhlidal CA, Rogan PK, Leeder JS. Development and refinement of pregnane X receptor (PXR) DNA binding site model using information theory: insights into PXR-mediated gene regulation. J Biol Chem. 2004;279:46779–86.PubMedGoogle Scholar
  130. 130.
    Xie W, Barwick JL, Simon CM, et al. Reciprocal activation of xenobiotic response genes by nuclear receptors SXR/PXR and CAR. Genes Dev. 2000;14:3014–23.PubMedGoogle Scholar
  131. 131.
    Wang K, Damjanov I, Wan YJ. The protective role of pregnane X receptor in lipopolysaccharide/D-galactosamine-induced acute liver injury. Lab Invest. 2009;90:257–65.PubMedGoogle Scholar
  132. 132.
    Sueyoshi T, Negishi M. Phenobarbital response elements of cytochrome P450 genes and nuclear receptors. Annu Rev Pharmacol Toxicol. 2001;41:123–43.PubMedGoogle Scholar
  133. 133.
    Choi HS, Chung M, Tzameli I, et al. Differential transactivation by two isoforms of the orphan nuclear hormone receptor CAR. J Biol Chem. 1997;272:23565–71.PubMedGoogle Scholar
  134. 134.
    Forman BM, Tzameli I, Choi HS, et al. Androstane metabolites bind to and deactivate the nuclear receptor CAR-beta. Nature. 1998;395:612–5.PubMedGoogle Scholar
  135. 135.
    Ledda-Columbano GM, Pibiri M, Cossu C, Molotzu F, Locker J, Columbano A. Aging does not reduce the hepatocyte proliferative response of mice to the primary mitogen TCPOBOP. Hepatology. 2004;40:981–8.PubMedGoogle Scholar
  136. 136.
    Locker J, Tian J, Carver R, et al. A common set of immediate-early response genes in liver regeneration and hyperplasia. Hepatology. 2003;38:314–25.PubMedGoogle Scholar
  137. 137.
    Wei P, Zhang J, Egan-Hafley M, Liang S, Moore DD. The nuclear receptor CAR mediates specific xenobiotic induction of drug metabolism. Nature. 2000;407:920–3.PubMedGoogle Scholar
  138. 138.
    Mangelsdorf DJ, Evans RM. The RXR heterodimers and orphan receptors. Cell. 1995;83:841–50.PubMedGoogle Scholar
  139. 139.
    de Lera AR, Bourguet W, Altucci L, Gronemeyer H. Design of selective nuclear receptor modulators: RAR and RXR as a case study. Nat Rev Drug Discov. 2007;6:811–20.PubMedGoogle Scholar
  140. 140.
    Mascrez B, Ghyselinck NB, Chambon P, Mark M. A transcriptionally silent RXRalpha supports early embryonic morphogenesis and heart development. Proc Natl Acad Sci USA. 2009;106:4272–7.PubMedGoogle Scholar
  141. 141.
    Wan YJ, An D, Cai Y, et al. Hepatocyte-specific mutation establishes retinoid X receptor alpha as a heterodimeric integrator of multiple physiological processes in the liver. Mol Cell Biol. 2000;20:4436–44.PubMedGoogle Scholar
  142. 142.
    Spear BT, Jin L, Ramasamy S, Dobierzewska A. Transcriptional control in the mammalian liver: liver development, perinatal repression, and zonal gene regulation. Cell Mol Life Sci. 2006;63:2922–38.PubMedGoogle Scholar
  143. 143.
    Liu B, Paranjpe S, Bowen WC, et al. Investigation of the role of glypican 3 in liver regeneration and hepatocyte proliferation. Am J Pathol. 2009;175:717–24.PubMedGoogle Scholar
  144. 144.
    Gargalovic PS, Erbilgin A, Kohannim O, et al. Quantitative trait locus mapping and identification of zhx2 as a novel regulator of plasma lipid metabolism. Circ Cardiovasc Genet. 2010;3:60–7.PubMedGoogle Scholar
  145. 145.
    Xie Z, Zhang H, Tsai W, et al. Zinc finger protein ZBTB20 is a key repressor of alpha-fetoprotein gene transcription in liver. Proc Natl Acad Sci U S A. 2008;105:10859–64.PubMedGoogle Scholar
  146. 146.
    Sutherland AP, Zhang H, Zhang Y, et al. Zinc finger protein Zbtb20 is essential for postnatal survival and glucose homeostasis. Mol Cell Biol. 2009;29:2804–15.PubMedGoogle Scholar
  147. 147.
    Viger RS, Guittot SM, Anttonen M, Wilson DB, Heikinheimo M. Role of the GATA family of transcription factors in endocrine development, function, and disease. Mol Endocrinol. 2008;22:781–98.PubMedGoogle Scholar
  148. 148.
    Coll M, Seidman JG, Muller CW. Structure of the DNA-bound T-box domain of human TBX3, a transcription factor responsible for ulnar-mammary syndrome. Structure. 2002;10:343–56.PubMedGoogle Scholar
  149. 149.
    Chen X, Taube JR, Simirskii VI, Patel TP, Duncan MK. Dual roles for Prox1 in the regulation of the chicken betaB1-crystallin promoter. Invest Ophthalmol Vis Sci. 2008;49:1542–52.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Department of PathologyAlbert Einstein College of MedicineNew YorkUSA

Personalised recommendations