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Identification of Farnesoid X Receptor ß as a Novel Mammalian Nuclear Receptor Sensing Lanosterol
Kerstin Otte,1* Harald Kranz,1 Ingo Kober,1 Paul Thompson,1 Michael Hoefer,1 Bernhard Haubold,1 Bettina Remmel,1 Hartmut Voss,1 Carmen Kaiser,1 Michael Albers,1 Zaccharias Cheruvallath,1 David Jackson,1 Georg Casari,1 Manfred Koegl,1 Svante Pääbo,2 Jan Mous,1 Claus Kremoser,1, and Ulrich Deuschle1,
LION Bioscience AG, 69120 Heidelberg,1
Max Planck Institute for Evolutionary Anthropology, 04103 Leipzig, Germany2
Received for publication 19 September 2002.
Revision received 31 October 2002.
Accepted for publication 12 November 2002.
Abstract:
Nuclear receptors are ligand-modulated transcription factors.On the basis of the completed human genome sequence, this familywas thought to contain 48 functional members. However, by mininghuman and mouse genomic sequences, we identified FXRßas a novel family member. It is a functional receptor in mice,rats, rabbits, and dogs but constitutes a pseudogene in humansand primates. Murine FXRß is widely coexpressed withFXR in embryonic and adult tissues. It heterodimerizes withRXR and stimulates transcription through specific DNA responseelements upon addition of 9-cis-retinoic acid. Finally, we identifiedlanosterol as a candidate endogenous ligand that induces coactivatorrecruitment and transcriptional activation by mFXRß.Lanosterol is an intermediate of cholesterol biosynthesis, whichsuggests a direct role in the control of cholesterol biosynthesisin nonprimates. The identification of FXRß as a novelfunctional receptor in nonprimate animals sheds new light onthe species differences in cholesterol metabolism and has strongimplications for the interpretation of genetic and pharmacologicalstudies of FXR-directed physiologies and drug discovery programs.
W. Fan, M. Downes, A. Atkins, R. Yu, and R. M. Evans (2011)
Cold Spring Harb Symp Quant Biol
76, 17-22
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Activation of Retinoic Acid Receptors by Dihydroretinoids.
A. R. Moise, S. Alvarez, M. Dominguez, R. Alvarez, M. Golczak, G. P. Lobo, J. von Lintig, A. R. de Lera, and K. Palczewski (2009)
Mol. Pharmacol.
76, 1228-1237
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Role of Bile Acids and Bile Acid Receptors in Metabolic Regulation.
P. Lefebvre, B. Cariou, F. Lien, F. Kuipers, and B. Staels (2009)
Physiol Rev
89, 147-191
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The Role of FXR in Disorders of Bile Acid Homeostasis.
Research Resource: Nuclear Hormone Receptor Expression in the Endocrine Pancreas.
J.-C. Chuang, J.-Y. Cha, J. C. Garmey, R. G. Mirmira, and J. J. Repa (2008)
Mol. Endocrinol.
22, 2353-2363
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Evolution of the bile salt nuclear receptor FXR in vertebrates.
E. J. Reschly, N. Ai, S. Ekins, W. J. Welsh, L. R. Hagey, A. F. Hofmann, and M. D. Krasowski (2008)
J. Lipid Res.
49, 1577-1587
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Analysis of Nuclear Receptor Pseudogenes in Vertebrates: How the Silent Tell Their Stories.
Z. D. Zhang, P. Cayting, G. Weinstock, and M. Gerstein (2008)
Mol. Biol. Evol.
25, 131-143
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The farnesoid X receptor FXR{alpha}/NR1H4 acquired ligand specificity for bile salts late in vertebrate evolution.
S.-Y. Cai, L. Xiong, C. G. Wray, N. Ballatori, and J. L. Boyer (2007)
Am J Physiol Regulatory Integrative Comp Physiol
293, R1400-R1409
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Regulation of Hepatic Insig-2 by the Farnesoid X Receptor.
M. L. Hubbert, Y. Zhang, F. Y. Lee, and P. A. Edwards (2007)
Mol. Endocrinol.
21, 1359-1369
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In Vivo Imaging of Farnesoid X Receptor Activity Reveals the Ileum as the Primary Bile Acid Signaling Tissue.
S. M. Houten, D. H. Volle, C. L. Cummins, D. J. Mangelsdorf, and J. Auwerx (2007)
Mol. Endocrinol.
21, 1312-1323
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Overview of Nomenclature of Nuclear Receptors.
P. Germain, B. Staels, C. Dacquet, M. Spedding, and V. Laudet (2006)
Pharmacol. Rev.
58, 685-704
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International Union of Pharmacology. LXII. The NR1H and NR1I Receptors: Constitutive Androstane Receptor, Pregnene X Receptor, Farnesoid X Receptor {alpha}, Farnesoid X Receptor beta, Liver X Receptor {alpha}, Liver X Receptor beta, and Vitamin D Receptor.
D. D. Moore, S. Kato, W. Xie, D. J. Mangelsdorf, D. R. Schmidt, R. Xiao, and S. A. Kliewer (2006)
Pharmacol. Rev.
58, 742-759
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The farnesoid x receptor is expressed in breast cancer and regulates apoptosis and aromatase expression..
K. E. Swales, M. Korbonits, R. Carpenter, D. T. Walsh, T. D. Warner, and D. Bishop-Bailey (2006)
Cancer Res.
66, 10120-10126
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The Nuclear Hormone Receptor Farnesoid X Receptor (FXR) Is Activated by Androsterone.
S. Wang, K. Lai, F. J. Moy, A. Bhat, H. B. Hartman, and M. J. Evans (2006)
Endocrinology
147, 4025-4033
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Oxysterol 22(R)-Hydroxycholesterol Induces the Expression of the Bile Salt Export Pump through Nuclear Receptor Farsenoid X Receptor but Not Liver X Receptor.
R. Deng, D. Yang, J. Yang, and B. Yan (2006)
J. Pharmacol. Exp. Ther.
317, 317-325
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The Farnesoid X Receptor: A Molecular Link Between Bile Acid and Lipid and Glucose Metabolism.
T. Claudel, B. Staels, and F. Kuipers (2005)
Arterioscler Thromb Vasc Biol
25, 2020-2030
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Lipid Signaling in Plants. Cloning and Expression Analysis of the Obtusifoliol 14{alpha}-Demethylase from Solanum chacoense Bitt., a Pollination- and Fertilization-Induced Gene with Both Obtusifoliol and Lanosterol Demethylase Activity.
M. O'Brien, S.-C. Chantha, A. Rahier, and D. P. Matton (2005)
Plant Physiology
139, 734-749
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Nuclear Receptor Signaling in the Control of Cholesterol Homeostasis: Have the Orphans Found a Home?.
Genomic Analysis of the Nuclear Receptor Family: New Insights Into Structure, Regulation, and Evolution From the Rat Genome.
Z. Zhang, P. E. Burch, A. J. Cooney, R. B. Lanz, F. A. Pereira, J. Wu, R. A. Gibbs, G. Weinstock, and D. A. Wheeler (2004)
Genome Res.
14, 580-590
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Expression and activation of the farnesoid X receptor in the vasculature.
D. Bishop-Bailey, D. T. Walsh, and T. D. Warner (2004)
PNAS
101, 3668-3673
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Peroxisome proliferator-activated receptor-{gamma} coactivator 1{alpha} (PGC-1{alpha}) regulates triglyceride metabolism by activation of the nuclear receptor FXR.
Y. Zhang, L. W. Castellani, C. J. Sinal, F. J. Gonzalez, and P. A. Edwards (2004)
Genes & Dev.
18, 157-169
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The first completed genome sequence from a teleost fish (Fugu rubripes) adds significant diversity to the nuclear receptor superfamily.
J. M. Maglich, J. A. Caravella, M. H. Lambert, T. M. Willson, J. T. Moore, and L. Ramamurthy (2003)
Nucleic Acids Res.
31, 4051-4058
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Present address: Phenex Pharmaceuticals AG, 69120 Heidelberg, Germany. 
and Ulrich Deuschle1
and stimulates transcription through specific DNA response elements upon addition of 9-cis-retinoic acid. Finally, we identified lanosterol as a candidate endogenous ligand that induces coactivator recruitment and transcriptional activation by mFXRß. Lanosterol is an intermediate of cholesterol biosynthesis, which suggests a direct role in the control of cholesterol biosynthesis in nonprimates. The identification of FXRß as a novel functional receptor in nonprimate animals sheds new light on the species differences in cholesterol metabolism and has strong implications for the interpretation of genetic and pharmacological studies of FXR-directed physiologies and drug discovery programs. 
