Identification of a selective agonist for liver X receptor α (LXRα) via screening of a synthetic compound library

J Biomol Screen. 2014 Apr;19(4):566-74. doi: 10.1177/1087057113516004. Epub 2013 Dec 13.

Abstract

Liver X receptor α (LXRα) plays an important role in reverse cholesterol transport (RCT), and activation of LXRα could reduce atherosclerosis. In the present study, we developed a screening method to identify new potential LXRα agonists using an LXRα-GAL4 chimera reporter assay. A novel analogue of N,N-disubstituted 2,8-diazaspiro[4.5]decane, IMB-151, was identified as an LXRα agonist by using this method. IMB-151 showed a significant activation effect on LXRα, with an EC50 value of 1.47 µM. IMB-151 also increased the expression of ATP-binding cassette transporter A1 (ABCA1) and G1 (ABCG1) in RAW264.7 macrophages. The upregulating effects of IMB-151 on ABCA1 and ABCG1 markedly decreased when coincubated with geranylgeranyl pyrophosphate (GGPP) ammonium salt or LXRα small interfering RNA (siRNA). Our data indicated that the upregulation of ABCA1 and ABCG1 by IMB-151 depended on activation of LXRα. Moreover, IMB-151 significantly reduced cellular lipid accumulation and increased cholesterol efflux in RAW264.7 macrophages. Interestingly, IMB-151 slightly increased sterol response element binding protein 1c (SREBP-1c) protein expression levels in HepG2 cells compared with TO901317, and this indicated that IMB-151 might have less lipogenesis side effect in vivo. These results suggested that IMB-151 was identified as a selective agonist for LXRα by using a screening method and could be used as a potential antiatherosclerotic lead compound in the future.

Keywords: ABCA1; ABCG1; LXRα; atherosclerosis; cholesterol efflux.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter 1 / genetics
  • ATP Binding Cassette Transporter 1 / metabolism
  • Animals
  • Cell Line
  • Cholesterol / metabolism
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Drug Evaluation, Preclinical / methods*
  • Gene Expression
  • Gene Expression Regulation / drug effects
  • Genes, Reporter
  • Humans
  • Ligands*
  • Lipid Metabolism / drug effects
  • Liver X Receptors
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Mice
  • Orphan Nuclear Receptors / agonists*
  • Orphan Nuclear Receptors / genetics
  • Orphan Nuclear Receptors / metabolism
  • Small Molecule Libraries*
  • Sterol Regulatory Element Binding Protein 1 / genetics
  • Sterol Regulatory Element Binding Protein 1 / metabolism

Substances

  • ATP Binding Cassette Transporter 1
  • Ligands
  • Liver X Receptors
  • NR1H3 protein, human
  • Nr1h3 protein, mouse
  • Orphan Nuclear Receptors
  • Small Molecule Libraries
  • Sterol Regulatory Element Binding Protein 1
  • Cholesterol