title: Identification of farnesoid X receptor beta as a novel mammalian nuclear receptor sensing lanosterol.
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 FXRbeta 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 FXRbeta is widely coexpressed with FXR in embryonic and adult tissues. It heterodimerizes with RXRalpha 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 mFXRbeta. Lanosterol is an intermediate of cholesterol biosynthesis, which suggests a direct role in the control of cholesterol biosynthesis in nonprimates. The identification of FXRbeta 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.
authors.affiliation: LION Bioscience AG, 69120 Heidelberg, Germany. kerstinotte@yahoo.de
authors.forename: Kerstin
authors.initials: K
authors.lastname: Otte
authors.forename: Harald
authors.initials: H
authors.lastname: Kranz
authors.forename: Ingo
authors.initials: I
authors.lastname: Kober
authors.forename: Paul
authors.initials: P
authors.lastname: Thompson
authors.forename: Michael
authors.initials: M
authors.lastname: Hoefer
authors.forename: Bernhard
authors.initials: B
authors.lastname: Haubold
authors.forename: Bettina
authors.initials: B
authors.lastname: Remmel
authors.forename: Hartmut
authors.initials: H
authors.lastname: Voss
authors.forename: Carmen
authors.initials: C
authors.lastname: Kaiser
authors.forename: Michael
authors.initials: M
authors.lastname: Albers
authors.forename: Zaccharias
authors.initials: Z
authors.lastname: Cheruvallath
authors.forename: David
authors.initials: D
authors.lastname: Jackson
authors.forename: Georg
authors.initials: G
authors.lastname: Casari
authors.forename: Manfred
authors.initials: M
authors.lastname: Koegl
authors.forename: Svante
authors.initials: S
authors.lastname: Pääbo
authors.forename: Jan
authors.initials: J
authors.lastname: Mous
authors.forename: Claus
authors.initials: C
authors.lastname: Kremoser
authors.forename: Ulrich
authors.initials: U
authors.lastname: Deuschle
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002784:Cholesterol / Q000378:metabolism; D003001:Cloning, Molecular; D018076:DNA, Complementary / Q000235:genetics; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D019281:Dimerization; D004285:Dogs; D006801:Humans; D007810:Lanosterol / Q000378:metabolism*; D008024:Ligands; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D011323:Primates; D020836:Protein Structure, Quaternary; D011544:Pseudogenes; D011817:Rabbits; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics* / Q000378:metabolism*; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D002784:Cholesterol; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D007810:Lanosterol; D008024:Ligands; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated