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Mol. Cell. Biol. 23 (3): 864-872

Copyright © 2003 by the American Society for Microbiology. All rights reserved.

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,{dagger} and Ulrich Deuschle1,{dagger}

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 family was thought to contain 48 functional members. However, by mining human and mouse genomic sequences, we identified FXRß as a novel family member. It is a functional receptor in mice, rats, rabbits, and dogs but constitutes a pseudogene in humans and primates. Murine FXRß is widely coexpressed with FXR in embryonic and adult tissues. It heterodimerizes with RXR{alpha} 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.


* Corresponding author. Mailing address: LION Bioscience AG, Im Neuenheimer Feld 515, 69120 Heidelberg, Germany. Phone: 49-6221-4038228. Fax: 49-6221-4038301. E-mail: kerstinotte{at}yahoo.de.

{dagger} Present address: Phenex Pharmaceuticals AG, 69120 Heidelberg, Germany.



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