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Hormone Signaling pp 283–304Cite as

Sensors for Metabolic Control

A Regulatory Network of Nuclear Receptors

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Part of the book series: Endocrine Updates ((ENDO,volume 17))

Abstract

Nuclear receptors are transcription factors characterized by two important properties: first, they are activated upon the binding of specific ligands for which they have high affinity and low capacity; second, they bind to specific response elements located in the vicinity of the promoter of their target genes (see Chapter 12). Thus, in a simplified view, the effector function of the nuclear receptors in a cell is to adapt the gene expression program according to the signals that they receive in form of specific ligands. Nuclear receptors share a common modular organization. A poorly structured N-terminal domain that may encompass a ligand-independent transactivation domain is followed by the DNA binding domain (DBD) comprised of two zinc fingers which is the hallmark of the nuclear receptor family. A hinge region then links the DNA binding domain to the ligand binding domain (LBD) that has a general fold structured by 12 α helices and 3 β sheets. Nuclear receptors bind to DNA in form of dimers, either homodimers or more often heterodimers with the receptor for 9-cis retinoic acid known as RXR. The DNA response element of nuclear receptors is formed of two sequences corresponding to or closely related to the hexamer AGGTCA. Their organisation in direct repeats or palindromic arrays and the length of the spacing between the two hexamers determine the specificity of these response elements towards each dimer of family members. The general scheme for transactivation via nuclear receptors is believed to occur in at least two steps. In the absence of ligand, the nuclear receptor dimer binds to a co-repressor protein that inhibits its transactivation properties. In the presence of ligand, or due to an alternative pathway of activation such as phosphorylation, the co-repressor is released and a coactivator is recruited, allowing further contacts to be made with the transcription machinery, eventually resulting in transcription enhancement (also see Chapters 12 and 13).

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References

  1. Desvergne B, Wahli W. 1999 Peroxisome proliferator-activated receptors: nuclear control of metabolism. Endocr Rev 20: 649–688.

    Article  PubMed  CAS  Google Scholar 

  2. Nuclear Receptors Nomenclature Committee. 1999 A unified nomenclature system for the nuclear receptor superfamily. Cell 97: 161–163.

    Article  Google Scholar 

  3. Juge-Aubry C, Pernin A, Favez T, Burger AG, Wahli W, Meier CA, Desvergne B. 1997 DNA binding properties of peroxisome proliferator-activated receptor subtypes on various natural peroxisome proliferator response elements: importance of the 5’ flanking region. J Biol Chem 272: 25252–25259.

    Article  PubMed  CAS  Google Scholar 

  4. Issemann I, Green S. 1990 Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators. Nature 347: 645–650.

    Article  PubMed  CAS  Google Scholar 

  5. Nolte RT, Wisely GB, Westin S, Cobb JE, Lambert MH, Kurokawa R, Rosenfeld MG, Willson TM, Glass CK, Millburn MV. 1998 Ligand binding and co-activator assembly of the peroxisome proliferator-activated receptor-y. Nature 395: 137–143.

    Article  PubMed  CAS  Google Scholar 

  6. Xu HE, Lambert MH, Montana VG, Parks DJ, Blanchard SG, Brown PJ, Sternbach DD, Lehmann JM, Wisely GB, Willson TM, Kliewer SA, Milburn MV. 1999 Molecular recognition of fatty acids by peroxisome proliferator-activated receptors. Mol Cell 3: 397–403.

    Article  PubMed  CAS  Google Scholar 

  7. Bourguet W, Ruff M, Chambon P, Gronemeyer H, Moras D. 1995 Crystal structure of the ligand-binding domain of the human nuclear receptor RXR-alpha. Nature 375: 377382.

    Google Scholar 

  8. Renaud JP, Rochel N, Ruff M, Vivat V, Chambon P, Gronemeyer H, Moras D. 1995 Crystal structure of the RAR-gamma ligand-binding domain bound to all-trans retinoic acid. Nature 378: 681–689.

    Article  PubMed  CAS  Google Scholar 

  9. Wagner RL, Apriletti JW, McGrath ME, West BL, Baxter JD, Fletterick RJ. 1995 A structural role for hormone in the thyroid hormone receptor. Nature 378: 690–697.

    Article  PubMed  CAS  Google Scholar 

  10. Braissant O, Foufelle F, Scotto C, Dauca M, Wahli W. 1996 Differential expression of peroxisome proliferator-activated receptors (PPARs): tissue distribution of PPAR-alpha,–beta, and -gamma in the adult rat. Endocrinology 137: 354–366.

    Article  PubMed  CAS  Google Scholar 

  11. Lee SS, Pineau T, Drago J, Lee EJ, Owens JW, Kroetz DL, Fernandez-Salguero PM, Westphal H, Gonzalez FJ. 1995 Targeted disruption of the a isoform of the peroxisome proliferator-activated receptor gene in mice results in abolishment of the pleiotropic effects of peroxisome proliferators. Mol Cell Biol 15: 3012–3022.

    PubMed  CAS  Google Scholar 

  12. Kersten S, Seydoux J, Peters JM, Gonzalez FJ, Desvergne B, Wahli W. 1999 Peroxisome proliferator-activated receptor a mediates the adaptive response to fasting. J Clin Invest 103: 1489–1498.

    Article  PubMed  CAS  Google Scholar 

  13. Leone T, Weinheimer C, Kelly D. 1999 A critical role for the peroxisome proliferatoractivated receptor a (PPARa) in the cellular fasting response: the PPARa-null mouse as a model of fatty acid oxidation disorders. Proc Natl Acad Sci USA 96: 7473–7478.

    Article  PubMed  CAS  Google Scholar 

  14. Rosen ED, Walkey CJ, Puigserver P, Spiegelman BM. 2000 Transcriptional regulation of adipogenesis. Genes Dev 14: 1293–1307.

    PubMed  CAS  Google Scholar 

  15. Barak Y, Nelson MC, Ong ES, Jones YZ, Ruiz-Lozano P, Chien KR, Koder A, Evans RM. 1999 PPAR gamma is required for placental, cardiac, and adipose tissue development. Mol Cell 4: 585–595.

    Article  PubMed  CAS  Google Scholar 

  16. Kubota N, Terauchi Y, Mild H, Tamemoto H, Yamauchi T, Komeda K, Satoh S, Nakano R, Ishii C, Sugiyama T, Eto K, Tsubamoto Y, Okuno A, Murakami K, Sekihara H, Hasegawa G, Naito M, Toyoshima Y, Tanaka S, Shiota K, Kitamura T, Fujita T, Ezaki O, Aizawa S, Kadowaki T, et al. 1999 PPAR gamma mediates high-fat diet-induced adipocyte hypertrophy and insulin resistance. Mol Cell 4: 597–609.

    Article  PubMed  CAS  Google Scholar 

  17. Kersten S, Desvergne B, Wahli W. 2000 Roles of PPARs in health and disease. Nature 405: 421–424.

    Google Scholar 

  18. Brown MS, Goldstein JL. 1999 A proteolytic pathway that controls the cholesterol content of membranes, cells, and blood. Proc Natl Acad Sci U S A 96: 11041–11048.

    Article  PubMed  CAS  Google Scholar 

  19. Song C, Kokontis JM, Hiipakka RA, Liao S. 1994 Ubiquitous receptor: a receptor that modulates gene activation by retinoic acid and thyroid hormone receptors. Proc. Natl. Acad. Sci. USA 91: 10809–10813.

    Google Scholar 

  20. Seol W, Choi HS, Moore DD. 1995 Isolation of proteins that interact specifically with the retinoid X receptor: two novel orphan receptors. Mol Endocrinol 9: 72–85.

    Article  PubMed  CAS  Google Scholar 

  21. Willy PJ, Umesono K, Ong ES, Evans RM, Heyman RA, Mangelsdorf DJ. 1995 LXR, a nuclear receptor that defines a distinct retinoid response pathway. Genes Dev 9: 10331045.

    Google Scholar 

  22. Teboul M, Enmark E, Li Q, Wikstrom AC, Pelto-Huikko M, Gustafsson JA. 1995 OR-1, a member of the nuclear receptor superfamily that interacts with the 9-cis-retinoic acid receptor. Proc Natl Acad Sci U S A 92: 2096–2100.

    Article  PubMed  CAS  Google Scholar 

  23. Repa JJ, Mangelsdorf DJ. 1999 Nuclear receptor regulation of cholesterol and bile acid metabolism. Cuff Opin Biotechnol 10: 557–563.

    Article  CAS  Google Scholar 

  24. Janowski BA, Willy PJ, Devi TR, Mangelsdorf DJ. 1996 An oxysterol signalling pathway mediated by the nuclear receptor LXRa. Nature 383: 728–731.

    Article  PubMed  CAS  Google Scholar 

  25. Peet DJ, Turley SD, Ma W, Janowski BA, Lobaccaro JM, Hammer RE, Mangelsdorf DJ. 1998 Cholesterol and bile acid metabolism are impaired in mice lacking the nuclear oxysterol receptor LXR alpha. Cell 93: 693–704.

    Article  PubMed  CAS  Google Scholar 

  26. Repa JJ, Turley SD, Lobaccaro JA, Medina J, Li L, Lustig K, Shan B, Heyman RA, Dietschy JM, Mangelsdorf DJ. 2000 Regulation of absorption and ABC1-mediated efflux of cholesterol by RXR heterodimers. Science 289: 1524–1529.

    Article  PubMed  CAS  Google Scholar 

  27. Forman BM, Goode E, Chen J, Oro AE, Bradley DJ, Perlmann T, Noonan DJ, Burka LT, McMorris T, Lamph WW, Evans RM, Weinberger C. 1995 Identification of a nuclear receptor that is activated by farnesol metabolites. Celi 81: 687–693.

    Article  CAS  Google Scholar 

  28. Makishima M, Okamoto AY, Repa JJ, Tu H, Learned RM, Luk A, Hull MV, Lustig KD, Mangelsdorf DJ, Shan B. 1999 Identification of a nuclear receptor for bile acids. Science 284: 1362–1365.

    Article  PubMed  CAS  Google Scholar 

  29. Parks DJ, Blanchard SG, Bledsoe RK, Chandra G, Consler TG, Kliewer SA, Stinunel JB, Willson TM, Zavacki AM, Moore DD, Lehmann JM. 1999 Bile acids: natural ligands for an orphan nuclear receptor. Science 284: 1365–1368.

    Article  PubMed  CAS  Google Scholar 

  30. Wang H, Chen J, Hollister K, Sowers LC, Forman BM. 1999 Endogenous bile acids are ligands for the nuclear receptor FXR/BAR. Mol Cell 3: 543–553.

    Article  PubMed  CAS  Google Scholar 

  31. Sinai CJ, Tohkin M, Miyata M, Ward JM, Lambert G, Gonzalez FJ. 2000 Targeted disruption of the nuclear receptor FXR/BAR impairs bile acid and lipid homeostasis. Cell 102: 731–744.

    Article  Google Scholar 

  32. Grober J, Zaghini I, Fujii H, Jones SA, Kliewer SA, Willson TM, Ono T, Besnard P. 1999 Identification of a bile acid-responsive element in the human ileal bile acid-binding protein gene. Involvement of the farnesoid X receptor/9-cis-retinoic acid receptor heterodimer. J Biol Chem 274: 29749–29754.

    Article  PubMed  CAS  Google Scholar 

  33. Goodwin B, Jones SA, Price RR, Watson MA, McKee DD, Moore LB, Galardi C, Wilson JG, Lewis MC, Roth ME, Maloney PR, Willson TM, Kliewer SA. 2000 A regulatory cascade of the nuclear receptors FXR, SHP-1, and LRH-1 represses bile acid biosynthesis. Mol Cell 6: 517–526.

    Article  PubMed  CAS  Google Scholar 

  34. Lu TT, Makishima M, Repa JJ, Schoonjans K, Kerr TA, Auwerx J, Mangelsdorf DJ. 2000 Molecular basis for feedback regulation of bile acid synthesis by nuclear receptors. Mol Cell 6: 507–515.

    Article  PubMed  CAS  Google Scholar 

  35. Seol W, Choi HS, Moore DD. 1996 An orphan nuclear hormone receptor that lacks a DNA binding domain and heterodimerizes with other receptors. Science 272: 1336–1339.

    Article  PubMed  CAS  Google Scholar 

  36. Parker KL, Schedl A, Schimmer BP. 1999 Gene interactions in gonadal development. Annu Rev Physiol 61: 417–433.

    Article  PubMed  CAS  Google Scholar 

  37. Coon MJ, Ding XX, Pernecky SJ, Vaz AD. 1992 Cytochrome P450: progress and predictions. FASEB J 6: 669–673.

    PubMed  CAS  Google Scholar 

  38. Waxman DJ. 1999 P450 gene induction by structurally diverse xenochemicals: central role of nuclear receptors CAR, PXR, and PPAR. Arch Biochem Biophys 369: 11–23.

    Article  PubMed  CAS  Google Scholar 

  39. Muerhoff AS, Griffin KJ, Johnson EF. 1992 The peroxisome proliferator-activated receptor mediates the induction of CYP4A6, a cytochrome-P450 fatty-acid omegahydroxylase, by clofibric acid. J Biol Chem 267: 19051–19053.

    PubMed  CAS  Google Scholar 

  40. Maurel P. 1996 The CYP3A family. In: Ioannides C (ed.), Cytochromes P450: Metabolic and Toxicological Aspects, CRC Press Inc., Boca Raton, FL, 241–270.

    Google Scholar 

  41. Kliewer SA, Moore JT, Wade L, Staudinger JL, Watson MA, Jones SA, McKee DD, Oliver BB, Willson TM, Zetterstrom RH, Perlmann T, Lehmann JM. 1998 An orphan nuclear receptor activated by pregnanes defines a novel steroid signaling pathway. Cell 92: 73–82.

    Article  PubMed  CAS  Google Scholar 

  42. Blumberg B, Sabbagh W, Jr., Juguilon H, Bolado J, Jr., van Meter CM, Ong ES, Evans RM. 1998 SXR, a novel steroid and xenobiotic-sensing nuclear receptor. Genes Dev 12: 3195–3205.

    Article  PubMed  CAS  Google Scholar 

  43. Bertilsson G, Heidrich J, Svensson K, Asman M, Jendeberg L, Sydow-Bäckman M, Ohlsson R, Postlind H, Blomquist P, Berkenstam A. 1998 Identification of a human nuclear receptor defines a new signaling pathway for CYP3A induction. Proc Natl Sci Acad Sci USA 95: 12208–12213.

    Article  CAS  Google Scholar 

  44. Lehmann JM, McKee DD, Watson MA, Willson TM, Moore JT, Kliewer SA. 1998 The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions. J Clin Invest 102: 1016–1023.

    Article  PubMed  CAS  Google Scholar 

  45. Jones SA, Moore LB, Shenk JL, Wisely GB, Hamilton GA, McKee DD, Tomkinson NC, LeCluyse EL, Lambert MH, Willson TM, Kliewer SA, Moore JT. 2000 The pregnane X receptor: a promiscuous xenobiotic receptor that has diverged during evolution. Mol Endocrinol 14: 27–39.

    Article  PubMed  CAS  Google Scholar 

  46. Xie W, Barwick JL, Downes M, Blumberg B, Simon CM, Nelson MC, Neuschwander-Tetri BA, Brunt EM, Guzelian PS, Evans RM. 2000 Humanized xenobiotic response in mice expressing nuclear receptor SXR. Nature 406: 435–439.

    Article  PubMed  CAS  Google Scholar 

  47. Baes M, Gulick T, Choi HS, Martinoli MG, Simha D, Moore DD. 1994 A new orphan member of the nuclear hormone receptor superfamily that interacts with a subset of retinoic acid response elements. Mol Cell Biol 14: 1544–1552.

    PubMed  CAS  Google Scholar 

  48. Choi HS, Chung M, Tzameli I, Simha D, Lee YK, Seol W, Moore DD. 1997 Differential transactivation by two isoforms of the orphan nuclear hormone receptor CAR. J Biol Chem 272: 23565–23571.

    Article  PubMed  CAS  Google Scholar 

  49. Tzameli I, Moore DD. 2001 Role reversal: new insights from new ligands for the xenobiotic receptor CAR. Trends Endocrinol Metab 12: 7–10.

    Article  PubMed  CAS  Google Scholar 

  50. Forman BM, Tzameli I, Choi HS, Chen J, Simha D, Seol W, Evans RM, Moore DD. 1998 Androstane metabolites bind to and deactivate the nuclear receptor CAR-beta. Nature 395: 612–615.

    Article  PubMed  CAS  Google Scholar 

  51. Sueyoshi T, Kawamoto T, Zelko I, Honkakoski P, Negishi M. 1999 The repressed nuclear receptor CAR responds to phenobarbital in activating the human CYP2B6 gene. J Biol Chem 274: 6043–6046.

    Article  PubMed  CAS  Google Scholar 

  52. Honkakoski P, Zelko I, Sueyoshi T, Negishi M. 1998 The nuclear orphan receptor CAR-retinoid X receptor heterodimer activates the phenobarbital-responsive enhancer module of the CYP2B gene. Mol Cell Biol 18: 5652–5658.

    PubMed  CAS  Google Scholar 

  53. Kawamoto T, Sueyoshi T, Zelko I, Moore R, Washburn K, Negishi M. 1999 Phenobarbital-responsive nuclear translocation of the receptor CAR in induction of the CYP2B gene. Mol Cell Biol 19: 6318–6322.

    PubMed  CAS  Google Scholar 

  54. Wei P, Zhang J, Egan-Hafley M, Liang S, Moore DD. 2000 The nuclear receptor CAR mediates specific xenobiotic induction of drug metabolism. Nature 407: 920–923.

    Article  PubMed  CAS  Google Scholar 

  55. Moore LB, Parks DJ, Jones SA, Bledsoe RK, Consler TG, Stimmel JB, Goodwin B, Liddle C, Blanchard SG, Willson TM, Collins JL, Kliewer SA. 2000 Orphan nuclear receptors constitutive androstane receptor and pregnane X receptor share xenobiotic and steroid ligands. J Biol Chem 275: 15122–15127.

    Article  PubMed  CAS  Google Scholar 

  56. Xie W, Barwick JL, Simon CM, Pierce AM, Safe S, Blumberg B, Guzelian PS, Evans RM. 2000 Reciprocal activation of xenobiotic response genes by nuclear receptors SXR/PXR and CAR. Genes Dev 14: 3014–3023.

    Article  PubMed  CAS  Google Scholar 

  57. Moore JT, Kliewer SA. 2000 Use of the nuclear receptor PXR to predict drug interactions. Toxicology 153: 1–10.

    Article  PubMed  CAS  Google Scholar 

  58. Mertz JR, Shang E, Piantedosi R, Wei S, Wolgemuth DJ, Blaner WS. 1997 Identification and characterization of a stereospecific human enzyme that catalyzes 9-cisretinol oxidation. A possible role in 9-cis-retinoic acid formation. J Biol Chem 272: 1174411749.

    Google Scholar 

  59. Romert A, Tuvendal P, Simon A, Dencker L, Eriksson U. 1998 The identification of a 9-cis retinol dehydrogenase in the mouse embryo reveals a pathway for synthesis of 9-cis retinoic acid. Proc Natl Acad Sci U S A 95: 4404–4409.

    Article  PubMed  CAS  Google Scholar 

  60. Bourguet W, Vivat V, Wurtz JM, Chambon P, Gronemeyer H, Moras D. 2000 Crystal structure of a heterodimeric complex of RAR and RXR ligand-binding domains. Mol Cell 5: 289–298.

    Article  PubMed  CAS  Google Scholar 

  61. de Urquiza AM, Liu S, Sjoberg M, Zetterstrom RH, Griffiths W, Sjovall J, Perlmann T. 2000 Docosahexaenoic acid, a ligand for the retinoid X receptor in mouse brain. Science 290: 2140–2144.

    Article  PubMed  Google Scholar 

  62. Mark M, Ghyselinck NB, Wendling O, Dupe V, Mascrez B, Kastner P, Chambon P. 1999 A genetic dissection of the retinoid signalling pathway in the mouse. Proc Nutr Soc 58: 609–613.

    Article  PubMed  CAS  Google Scholar 

  63. Wendling O, Chambon P, Mark M. 1999 Retinoid X receptors are essential for early mouse development and placentogenesis. Proc Natl Acad Sci U S A 96: 547–551.

    Article  PubMed  CAS  Google Scholar 

  64. Wan YJ, An D, Cai Y, Repa JJ, Hung-Po Chen T, Flores M, Postic C, Magnuson MA, Chen J, Chien KR, French S, Mangelsdorf DJ, Sucov HM. 2000 Hepatocytespecific mutation establishes retinoid X receptor alpha as a heterodimeric integrator of multiple physiological processes in the liver. Mol Cell Biol 20: 4436–4444.

    Article  PubMed  CAS  Google Scholar 

  65. Keller H, Devchand PR, Perroud M, Wahli W. 1997 PPAR alpha structure-function relationships derived from species-specific differences in responsiveness to hypolipidemic agents. Biol Chem 378: 651–655.

    Article  PubMed  CAS  Google Scholar 

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  1. Institute of Animal Biology, Faculty of Sciences, University of Lausanne, Bâtiment Biologie, CH- 1015, Lausanne, Switzerland

    Béatrice Desvergne, Liliane Michalik & Walter Wahli

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  1. Béatrice Desvergne
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  2. Liliane Michalik
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  1. Inserm Unit 344, Molecular Endocrinology, Faculty of Medicine Necker, Paris, France

    Vincent Goffin PhD  & Paul A. Kelly PhD  & 

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Desvergne, B., Michalik, L., Wahli, W. (2002). Sensors for Metabolic Control. In: Goffin, V., Kelly, P.A. (eds) Hormone Signaling. Endocrine Updates, vol 17. Springer, Boston, MA. https://doi.org/10.1007/978-1-4757-3600-7_14

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  • DOI: https://doi.org/10.1007/978-1-4757-3600-7_14

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