title: A natural product ligand of the oxysterol receptor, liver X receptor.
abstract: Natural products have been identified as ligands for a number of members of the nuclear hormone receptor (NHR) superfamily. Often these natural products are used as dietary supplements to treat myriad ailments ranging from perimenopausal hot flashes to hypercholesterolemia and reduced cognitive function. Examples of some natural product ligands for NHRs include genestein (estrogen receptors NR3A1 and NR3A2), guggulsterone (farnesoid X receptor NR1H4), and St. John's wort (pregnane X receptor, NR1I2). In this study, we identified the first nonoxysterol natural product that functions as a ligand for the liver X receptor (LXRalpha and LXRbeta; NR1H3, NR1H2), a NHR that acts as the receptor for oxysterols and plays a key role in regulation of cholesterol metabolism and transport as well as glucose metabolism. We show that paxilline, a fungal metabolite, is an efficacious agonist of both LXRalpha and LXRbeta in biochemical and in vitro cell-based assays. Paxilline binds directly to both receptors and is an activator of LXR-dependent transcription in cell-based reporter assays. We also demonstrate that paxilline binding to the receptors results in efficient activation of transcription of two physiological LXR target genes, ABCA1 and SREBP. The discovery of paxilline, the first reported nonoxysterol natural product ligand of the LXRs, may provide insight into the mechanism of ligand recognition by these receptors and reaffirms the utility of examining natural product libraries for identifying novel NHR ligands.
authors.affiliation: Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana 46060, USA.
authors.forename: Kelli S
authors.initials: KS
authors.lastname: Bramlett
authors.forename: Keith A
authors.initials: KA
authors.lastname: Houck
authors.forename: Kristen M
authors.initials: KM
authors.lastname: Borchert
authors.forename: Michele S
authors.initials: MS
authors.lastname: Dowless
authors.forename: Palaniappan
authors.initials: P
authors.lastname: Kulanthaivel
authors.forename: Youyan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Beyer
authors.forename: Robert
authors.initials: R
authors.lastname: Schmidt
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Thomas
authors.forename: Laura F
authors.initials: LF
authors.lastname: Michael
authors.forename: Robert
authors.initials: R
authors.lastname: Barr
authors.forename: Chahrzad
authors.initials: C
authors.lastname: Montrose
authors.forename: Patrick I
authors.initials: PI
authors.lastname: Eacho
authors.forename: Guoqing
authors.initials: G
authors.lastname: Cao
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Burris
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000032:analysis; D001685:Biological Factors / Q000494:pharmacology; D002478:Cells, Cultured; D004268:DNA-Binding Proteins; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D008024:Ligands; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000378:metabolism; D011987:Receptors, Steroid / Q000819:agonists* / Q000378:metabolism; D014162:Transfection; D000098825:Oxysterol Binding Proteins
chemical_list: C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D001685:Biological Factors; D004268:DNA-Binding Proteins; D007211:Indoles; D008024:Ligands; D000071518:Liver X Receptors; C000605210:NR1H2 protein, human; C000605213:NR1H3 protein, human; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D000098825:Oxysterol Binding Proteins; C048220:paxilline