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

Robert J. Schmidt, James V. Ficorilli, Youyan Zhang, Kelli S. Bramlett, Thomas P. Beyer, Kristen Borchert, Michele S. Dowless, Keith A. Houck, Thomas P. Burris, Patrick I. Eacho, Guosheng Liang, Li Wei Guo, William K. Wilson, Laura F. Michael, Guoqing Cao

Research output: Contribution to journalArticle

15 Scopus citations

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 3β-hydroxy-5α-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-α and -β (LXRα and LXRβ). 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 sterolresponsive 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.

Original languageEnglish (US)
Pages (from-to)1037-1044
Number of pages8
JournalJournal of Lipid Research
Volume47
Issue number5
DOIs
Publication statusPublished - May 2006

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Keywords

  • Hypercholesterolemia
  • Scintillation proximity assay
  • Statin

ASJC Scopus subject areas

  • Endocrinology

Cite this

Schmidt, R. J., Ficorilli, J. V., Zhang, Y., Bramlett, K. S., Beyer, T. P., Borchert, K., ... Cao, G. (2006). A 15-ketosterol is a liver X receptor ligand that suppresses sterol-responsive element binding protein-2 activity. Journal of Lipid Research, 47(5), 1037-1044. https://doi.org/10.1194/jlr.M500526-JLR200