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Molecular Pharmacology

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Research ArticleArticle

Identification of 5α,6α-Epoxycholesterol as a Novel Modulator of Liver X Receptor Activity

Thomas J. Berrodin, Qi Shen, Elaine M. Quinet, Matthew R. Yudt, Leonard P. Freedman and Sunil Nagpal
Molecular Pharmacology December 2010, 78 (6) 1046-1058; DOI: https://doi.org/10.1124/mol.110.065193
Thomas J. Berrodin
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Qi Shen
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Elaine M. Quinet
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Matthew R. Yudt
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Leonard P. Freedman
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Sunil Nagpal
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Abstract

The liver X receptors (LXRα and LXRβ) are members of the nuclear receptor superfamily that function as key transcriptional regulators of a number of biological processes, including cholesterol homeostasis, lipid metabolism, and keratinocyte differentiation. Natural ligands that activate LXRs include oxysterol derivatives such as 25-hydroxycholesterol, 27-hydroxycholesterol, 22(R)-hydroxycholesterol, 20(S)-hydroxycholesterol, and 24(S),25-epoxycholesterol. Related oxysterols, such as 5α,6α-epoxycholesterol (5,6-EC) are present in a number of foods and have been shown to induce atherosclerosis in animal models. Intriguingly, these oxysterols have also been detected in atherosclerotic plaques. Using a variety of biochemical and cellular assays, we demonstrate that 5,6-EC is the first dietary modulator and an endogenous LXR ligand with cell and gene context-dependent antagonist, agonist, and inverse agonist activities. In a multiplexed LXR-cofactor peptide interaction assay, 5,6-EC induced the recruitment of a number of cofactor peptides onto both LXRα and LXRβ and showed an EC50 of approximately 2 μM in peptide recruitment. Furthermore, 5,6-EC bound to LXRα in a radiolabeled ligand displacement assay (EC50 = 76 nM), thus demonstrating it to be one of the most potent natural LXRα ligands known to date. Analysis of endogenous gene expression in various cell-based systems indicated the potential of 5,6-EC to antagonize LXR-mediated gene expression. Furthermore, it also induced the expression of some LXR-responsive genes in keratinocytes. These results clearly demonstrate that 5,6-EC is an LXR modulator that may play a role in the development of lipid disorders, such as atherosclerosis, by antagonizing the agonistic action of endogenous LXR ligands.

Footnotes

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    doi:10.1124/mol.110.065193.

  • ABBREVIATIONS:

    LXR
    liver X receptor
    ABCA1
    ATP-binding cassette family transporter A1
    ACACA
    acetyl-coenzyme A carboxylase α
    Apo
    apolipoprotein
    EC
    epoxycholesterol
    FASN
    fatty acid synthase
    Ivl
    involucrin
    KO
    knockout
    LBD
    ligand binding domain
    LDLR
    low density lipoprotein receptor
    MFI
    mean fluorescence intensity
    NRIP
    nuclear receptor interacting protein
    OHC
    hydroxycholesterol
    PLTP
    phospholipid transfer protein
    SCD
    steroyl CoA desaturase
    SMRT
    silencing mediator of retinoic acid and thyroid hormone receptor
    SRC
    steroid receptor coactivator
    SREBF
    sterol response element binding factor
    VDR
    vitamin D receptor
    wt
    wild type
    PCR
    polymerase chain reaction
    FBS
    fetal bovine serum
    TLDA
    TaqMan Low-Density Array
    NF-κB
    nuclear factor κB
    ATCC
    American Type Culture Collection
    PMSF
    phenylmethylsulfonyl fluoride
    CHAPS
    3-[(3-cholamidopropyl)dimethylammonio]propanesulfonate
    GST
    glutathione transferase
    T0901317
    N-(2,2,2-trifluoroethyl)-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]-benzenesulfonamide
    MTG
    monothioglycerol.

  • Received March 30, 2010.
  • Accepted September 13, 2010.
  • Copyright © 2010 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 78 (6)
Molecular Pharmacology
Vol. 78, Issue 6
1 Dec 2010
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Research ArticleArticle

Identification of 5α,6α-Epoxycholesterol as a Novel Modulator of Liver X Receptor Activity

Thomas J. Berrodin, Qi Shen, Elaine M. Quinet, Matthew R. Yudt, Leonard P. Freedman and Sunil Nagpal
Molecular Pharmacology December 1, 2010, 78 (6) 1046-1058; DOI: https://doi.org/10.1124/mol.110.065193

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Research ArticleArticle

Identification of 5α,6α-Epoxycholesterol as a Novel Modulator of Liver X Receptor Activity

Thomas J. Berrodin, Qi Shen, Elaine M. Quinet, Matthew R. Yudt, Leonard P. Freedman and Sunil Nagpal
Molecular Pharmacology December 1, 2010, 78 (6) 1046-1058; DOI: https://doi.org/10.1124/mol.110.065193
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