PUBLICATION
Ligand specificity and evolution of liver X receptors
- Authors
- Reschly, E.J., Ai, N., Welsh, W.J., Ekins, S., Hagey, L.R., and Krasowski, M.D.
- ID
- ZDB-PUB-080414-13
- Date
- 2008
- Source
- The Journal of steroid biochemistry and molecular biology 110(1-2): 83-94 (Journal)
- Registered Authors
- Keywords
- oxysterols, nuclear hormone receptors, Urochordata, structure-activity relationship, molecular models, androstanes, pregnanes
- MeSH Terms
-
- Androstenes/chemistry
- Androstenes/pharmacology
- Animals
- Benzoates/chemistry
- Benzoates/pharmacology
- Benzylamines/chemistry
- Benzylamines/pharmacology
- Carbazoles/chemistry
- Carbazoles/pharmacology
- Cell Line, Tumor
- Cholesterol/analogs & derivatives
- Cholesterol/chemistry
- Cholesterol/pharmacology
- Ciona intestinalis
- DNA-Binding Proteins/agonists*
- DNA-Binding Proteins/genetics*
- DNA-Binding Proteins/metabolism
- Evolution, Molecular*
- Humans
- Hydrocarbons, Fluorinated
- Hydroxycholesterols/chemistry
- Hydroxycholesterols/pharmacology
- Mice
- Molecular Structure
- Orphan Nuclear Receptors
- Phylogeny
- Receptors, Cytoplasmic and Nuclear/agonists*
- Receptors, Cytoplasmic and Nuclear/genetics*
- Receptors, Cytoplasmic and Nuclear/metabolism
- Structure-Activity Relationship
- Sulfonamides/chemistry
- Sulfonamides/pharmacology
- Xenopus laevis
- Zebrafish
- PubMed
- 18395439 Full text @ Steroid Biochem. Mol. Biol.
Citation
Reschly, E.J., Ai, N., Welsh, W.J., Ekins, S., Hagey, L.R., and Krasowski, M.D. (2008) Ligand specificity and evolution of liver X receptors. The Journal of steroid biochemistry and molecular biology. 110(1-2):83-94.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping