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Molecular Pharmacology

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Research ArticleArticle

Regulation of Sphingomyelin Phosphodiesterase Acid-Like 3A Gene (SMPDL3A) by Liver X Receptors

Paul B. Noto, Yuri Bukhtiyarov, Meng Shi, Brian M. McKeever, Gerard M. McGeehan and Deepak S. Lala
Molecular Pharmacology October 2012, 82 (4) 719-727; DOI: https://doi.org/10.1124/mol.112.078865
Paul B. Noto
Discovery Biology, Vitae Pharmaceuticals, Inc., Fort Washington, Pennsylvania (P.B.N., Y.B., M.S., B.M.M., G.M.M., D.S.L.); and Department of Biology, Drexel University, Philadelphia, Pennsylvania (P.B.N.)
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Yuri Bukhtiyarov
Discovery Biology, Vitae Pharmaceuticals, Inc., Fort Washington, Pennsylvania (P.B.N., Y.B., M.S., B.M.M., G.M.M., D.S.L.); and Department of Biology, Drexel University, Philadelphia, Pennsylvania (P.B.N.)
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Meng Shi
Discovery Biology, Vitae Pharmaceuticals, Inc., Fort Washington, Pennsylvania (P.B.N., Y.B., M.S., B.M.M., G.M.M., D.S.L.); and Department of Biology, Drexel University, Philadelphia, Pennsylvania (P.B.N.)
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Brian M. McKeever
Discovery Biology, Vitae Pharmaceuticals, Inc., Fort Washington, Pennsylvania (P.B.N., Y.B., M.S., B.M.M., G.M.M., D.S.L.); and Department of Biology, Drexel University, Philadelphia, Pennsylvania (P.B.N.)
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Gerard M. McGeehan
Discovery Biology, Vitae Pharmaceuticals, Inc., Fort Washington, Pennsylvania (P.B.N., Y.B., M.S., B.M.M., G.M.M., D.S.L.); and Department of Biology, Drexel University, Philadelphia, Pennsylvania (P.B.N.)
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Deepak S. Lala
Discovery Biology, Vitae Pharmaceuticals, Inc., Fort Washington, Pennsylvania (P.B.N., Y.B., M.S., B.M.M., G.M.M., D.S.L.); and Department of Biology, Drexel University, Philadelphia, Pennsylvania (P.B.N.)
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Abstract

Liver X receptor (LXR) α and LXRβ function as physiological sensors of cholesterol metabolites (oxysterols), regulating key genes involved in cholesterol and lipid metabolism. LXRs have been extensively studied in both human and rodent cell systems, revealing their potential therapeutic value in the contexts of atherosclerosis and inflammatory diseases. The LXR genome landscape has been investigated in murine macrophages but not in human THP-1 cells, which represent one of the frequently used monocyte/macrophage cell systems to study immune responses. We used a whole-genome screen to detect direct LXR target genes in THP-1 cells treated with two widely used LXR ligands [N-(2,2,2-trifluoroethyl)-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)-ethyl]phenyl]-benzenesulfonamide (T0901317) and 3-[3-[N-(2-chloro-3-trifluoromethylbenzyl)-(2,2-diphenylethyl)amino]propyloxy] phenylacetic acid hydrochloride (GW3965)]. This screen identified the sphingomyelin phosphodiesterase acid-like 3A (SMPDL3A) gene as a novel LXR-regulated gene, with an LXR response element within its promoter. We investigated the regulation of SMPDL3A gene expression by LXRs across several human and mouse cell types. These studies indicate that the induction of SMPDL3A is LXR-dependent and is restricted to human blood cells with no induction observed in mouse cellular systems.

Footnotes

  • ↵Embedded Image The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.

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

    http://dx.doi.org/10.1124/mol.112.078865.

  • ABBREVIATIONS:

    LXR
    liver X receptor
    ABC
    ATP-binding cassette
    SREBP1c
    sterol regulatory element-binding protein-1c
    IL
    interleukin
    LPS
    lipopolysaccharide
    LXRE
    liver X receptor response element
    DR-4
    direct repeats separated by any four nucleotides
    SMPDL3A
    sphingomyelin phosphodiesterase acid-like 3A
    PMA
    phorbol 12-myristate 13-acetate
    HEK
    human embryonic kidney
    siRNA
    small interfering RNA
    PBS
    phosphate-buffered saline
    GW3965
    3-[3-[N-(2-chloro-3-trifluoromethylbenzyl)-(2,2-diphenylethyl)amino]propyloxy]phenylacetic acid hydrochloride
    T0901317
    N-(2,2,2-trifluoroethyl)-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)-ethyl]phenyl]-benzenesulfonamide
    LG100268
    2-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)cyclopropyl]pyridine-5-carboxylic acid
    DMSO
    dimethyl sulfoxide
    PCR
    polymerase chain reaction
    PBMC
    peripheral blood mononuclear cell
    RT
    real time
    HRP
    horseradish peroxidase
    RXR
    retinoid X receptor
    EMSA
    electrophoretic mobility shift assay
    ChIP
    chromatin immunoprecipitation
    CLL
    chemokine (C-C motif) ligand.

  • Received March 22, 2012.
  • Accepted July 11, 2012.
  • Copyright © 2012 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 82 (4)
Molecular Pharmacology
Vol. 82, Issue 4
1 Oct 2012
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Research ArticleArticle

Regulation of SMPDL3A by LXRs

Paul B. Noto, Yuri Bukhtiyarov, Meng Shi, Brian M. McKeever, Gerard M. McGeehan and Deepak S. Lala
Molecular Pharmacology October 1, 2012, 82 (4) 719-727; DOI: https://doi.org/10.1124/mol.112.078865

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Research ArticleArticle

Regulation of SMPDL3A by LXRs

Paul B. Noto, Yuri Bukhtiyarov, Meng Shi, Brian M. McKeever, Gerard M. McGeehan and Deepak S. Lala
Molecular Pharmacology October 1, 2012, 82 (4) 719-727; DOI: https://doi.org/10.1124/mol.112.078865
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