Ligand specificity and evolution of liver X receptors

Erica J Reschly; Ni Ai; William J Welsh; Sean Ekins; Lee R Hagey; Matthew D Krasowski

doi:10.1016/j.jsbmb.2008.02.007

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Ligand specificity and evolution of liver X receptors

Journal article

Peer reviewed

Ligand specificity and evolution of liver X receptors

Erica J Reschly, Ni Ai, William J Welsh, Sean Ekins, Lee R Hagey and Matthew D Krasowski

The Journal of steroid biochemistry and molecular biology, Vol.110(1), pp.83-94

2008

DOI: 10.1016/j.jsbmb.2008.02.007

PMCID: PMC2519238

PMID: 18395439

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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 LXRα and LXRβ 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.

Nuclear hormone receptors

Androstanes

Oxysterols

Pregnanes

Molecular models

Structure–activity relationship

Urochordata

Details

Title: Subtitle: Ligand specificity and evolution of liver X receptors
Creators: Erica J Reschly - Department of Pathology, University of Pittsburgh, Pittsburgh, PA, United States
Ni Ai - Department of Pharmacology, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway, NJ, United States
William J Welsh - Department of Pharmacology, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway, NJ, United States
Sean Ekins - Department of Pharmacology, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway, NJ, United States
Lee R Hagey - Department of Medicine, University of California, San Diego, CA, United States
Matthew D Krasowski - Department of Pathology, University of Pittsburgh, Pittsburgh, PA, United States
Resource Type: Journal article
Publication Details: The Journal of steroid biochemistry and molecular biology, Vol.110(1), pp.83-94
DOI: 10.1016/j.jsbmb.2008.02.007
PMID: 18395439
PMCID: PMC2519238
NLM abbreviation: J Steroid Biochem Mol Biol
ISSN: 0960-0760
eISSN: 1879-1220
Publisher: Elsevier Ltd
Language: English
Date published: 2008
Academic Unit: Pathology
Record Identifier: 9984047610802771

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