title: Ligand specificity and evolution of liver X receptors.
abstract: Liver X receptors (LXRs) are key regulators of lipid and cholesterol metabolism in mammals. Little is known, however, about the function and evolution of LXRs in non-mammalian species. The present study reports the cloning of LXRs from African clawed frog (Xenopus laevis), Western clawed frog (Xenopus tropicalis), and zebrafish (Danio rerio), and their functional characterization and comparison with human and mouse LXRs. Additionally, an ortholog of LXR in the chordate invertebrate Ciona intestinalis was cloned and functionally characterized. Ligand specificities of the frog and zebrafish LXRs were very similar to LXRalpha and LXRbeta from human and mouse. All vertebrate LXRs studied were activated robustly by the synthetic ligands T-0901317 and GW3965 and by a variety of oxysterols. In contrast, Ciona LXR was not activated by T-0901317 or GW3965 but was activated by a limited number of oxysterols, as well as some androstane and pregnane steroids. Pharmacophore analysis, homology modeling, and docking studies of Ciona LXR predict a receptor with a more restricted ligand-binding pocket and less intrinsic disorder in the ligand-binding domain compared to vertebrate LXRs. The results suggest that LXRs have a long evolutionary history, with vertebrate LXRs diverging from invertebrate LXRs in ligand specificity.
authors.affiliation: Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15261, United States.
authors.forename: Erica J
authors.initials: EJ
authors.lastname: Reschly
authors.forename: Ni
authors.initials: N
authors.lastname: Ai
authors.forename: William J
authors.initials: WJ
authors.lastname: Welsh
authors.forename: Sean
authors.initials: S
authors.lastname: Ekins
authors.forename: Lee R
authors.initials: LR
authors.lastname: Hagey
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Krasowski
mesh_terms: D000736:Androstenes / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001565:Benzoates / Q000737:chemistry / Q000494:pharmacology; D001596:Benzylamines / Q000737:chemistry / Q000494:pharmacology; D002227:Carbazoles / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D002938:Ciona intestinalis; D004268:DNA-Binding Proteins / Q000819:agonists* / Q000235:genetics* / Q000378:metabolism; D019143:Evolution, Molecular; D006801:Humans; D006845:Hydrocarbons, Fluorinated; D006888:Hydroxycholesterols / Q000737:chemistry / Q000494:pharmacology; D000071518:Liver X Receptors; D051379:Mice; D015394:Molecular Structure; D057093:Orphan Nuclear Receptors; D010802:Phylogeny; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000235:genetics* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology; D014982:Xenopus laevis; D015027:Zebrafish; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
chemical_list: D000736:Androstenes; D001565:Benzoates; D001596:Benzylamines; D002227:Carbazoles; D002784:Cholesterol; D004268:DNA-Binding Proteins; D006845:Hydrocarbons, Fluorinated; D006888:Hydroxycholesterols; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D013449:Sulfonamides; C111855:6-formylindolo(3,2-b)carbazole; C473027:GW 3965; C000605213:NR1H3 protein, human; C000605214:Nr1h3 protein, mouse; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides; C000214:androst-16-en-3-one; C028358:24,25-epoxycholesterol; C007997:25-hydroxycholesterol