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Reverse Yeast Two-hybrid System to Identify Mammalian Nuclear Receptor Residues that Interact with Ligands and/or Antagonists
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Gene-selective modulation by a synthetic oxysterol ligand of the liver X receptor

Elaine M Quinet1, Dawn A Savio, Anita R Halpern

  • 1Departments of Cardiovascular/Metabolic Diseases, Wyeth Research, Collegeville, PA 19246, USA. quinete@wyeth.com

Journal of Lipid Research
|August 5, 2004
PubMed

Insights

A new compound, DMHCA, selectively targets Liver X Receptors (LXRs) to enhance cholesterol removal without increasing triglycerides. This offers a potential new strategy for treating atherosclerosis and cardiovascular disease.

Area of Science:

  • Biochemistry
  • Pharmacology
  • Molecular Biology

Background:

  • Liver X receptors (LXRs) regulate cholesterol homeostasis and are targets for cardiovascular disease treatment.
  • LXR activation promotes cholesterol efflux but can also increase lipogenesis via SREBP-1c, posing a potential risk.
  • Developing gene-selective LXR modulators is crucial for therapeutic applications.

Purpose of the Study:

  • To investigate the potential of a novel synthetic oxysterol, N,N-dimethyl-3beta-hydroxycholenamide (DMHCA), as a gene-selective LXR modulator.
  • To evaluate DMHCA's ability to upregulate atheroprotective genes like ABCA1 while minimizing lipogenic effects.
  • To assess DMHCA's efficacy in promoting cholesterol efflux from macrophages and its potential in treating atherosclerosis.

Main Methods:

  • In vitro and in vivo studies in mice using the synthetic oxysterol DMHCA.
  • Analysis of gene expression, including ABCA1 and SREBP-1c, in response to DMHCA.
  • Assessment of cholesterol efflux from macrophages and plasma triglyceride levels.

Main Results:

  • DMHCA demonstrated potent activation of ABCA1 gene expression with minimal impact on SREBP-1c.
  • DMHCA effectively stimulated cholesterol transport in liver, small intestine, and peritoneal macrophages.
  • DMHCA enhanced macrophage cholesterol efflux and showed potential to inhibit cholesterol accumulation without altering plasma triglycerides.

Conclusions:

  • DMHCA acts as a gene-selective LXR modulator, upregulating ABCA1 while sparing SREBP-1c.
  • DMHCA's ability to promote cholesterol efflux and inhibit accumulation offers therapeutic potential for atherosclerosis.
  • DMHCA and similar selective LXR ligands represent promising avenues for studying and treating cardiovascular disease.

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