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A 15-ketosterol is a liver X receptor ligand that suppresses sterol-responsive element binding protein-2 activity

Academic Article
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Overview

authors

  • Schmidt, R. J.
  • Ficorilli, J. V.
  • Zhang, Y. Y.
  • Bramlett, K. S.
  • Beyer, T. P.
  • Borchert, K.
  • Dowless, M. S.
  • Houck, K. A.
  • Burris, Thomas
  • Eacho, P. I.
  • Liang, G. S.
  • Guo, L. W.
  • Wilson, W. Y.
  • Michael, L. F.
  • Cao, G. Q.

publication date

  • May 2006

journal

  • Journal of Lipid Research  Journal

abstract

  • Hypercholesterolemia is a major risk factor for coronary artery disease. Oxysterols are known to inhibit cholesterol biosynthesis and have been explored as potential antihypercholesterolemic agents. The ability of 3beta-hydroxy-5alpha-cholest-8(14)-en-15-one (15-ketosterol) to lower non-HDL cholesterol has been demonstrated in rodent and primate models, but the mechanisms of action remain poorly understood. Here we show in a coactivator recruitment assay and cotransfection assays that the 15-ketosterol is a partial agonist for liver X receptor-alpha and -beta (LXRalpha and LXRbeta). The binding affinity for the LXRs was comparable to those of native oxysterols. In a macrophage cell line of human origin, the 15-ketosterol elevated ATP binding cassette transporter ABCA1 mRNA in a concentration-dependent fashion with a potency similar to those of other oxysterols. We further found that in human embryonic kidney HEK 293 cells, the 15-ketosterol suppressed sterol-responsive element binding protein processing activity and thus inhibited mRNA expression of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, LDL receptor, and PCSK9. Our data thus provide a molecular basis for the hypocholesterolemic activity of the 15-ketosterol and further suggest its potential antiatherosclerotic benefit as an LXR agonist.

subject areas

  • ATP Binding Cassette Transporter 1
  • ATP-Binding Cassette Transporters
  • Cells, Cultured
  • Cholestenones
  • DNA-Binding Proteins
  • Gene Expression Regulation
  • Humans
  • Hydroxymethylglutaryl CoA Reductases
  • Liver X Receptors
  • Orphan Nuclear Receptors
  • Proprotein Convertase 9
  • Proprotein Convertases
  • Receptors, Cytoplasmic and Nuclear
  • Serine Endopeptidases
  • Sterol Regulatory Element Binding Protein 2
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Research

keywords

  • hypercholesterolemia
  • proximity assay
  • scintillation
  • statin
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Identity

International Standard Serial Number (ISSN)

  • 0022-2275

Digital Object Identifier (DOI)

  • 10.1194/jlr.M500526-JLR200

PubMed ID

  • 16415294
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Additional Document Info

start page

  • 1037

end page

  • 1044

volume

  • 47

issue

  • 5

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