title: Foam cell specific LXRα ligand.
abstract: OBJECTIVE
  The liver X receptor α (LXRα) is a ligand-dependent nuclear receptor and the major regulator of reverse cholesterol transport in macrophages. This makes it an interesting target for mechanistic study and treatment of atherosclerosis.
  
  
  RESULTS
  We optimized a promising stilbenoid structure (STX4) in order to reach nanomolar effective concentrations in LXRα reporter-gene assays. STX4 displayed the unique property to activate LXRα effectively but not its subtype LXRβ. The potential of STX4 to increase transcriptional activity as an LXRα ligand was tested with gene expression analyses in THP1-derived human macrophages and oxLDL-loaded human foam cells. Only in foam cells but not in macrophage cells STX4 treatment showed athero-protective effects with similar potency as the synthetic LXR ligand T0901317 (T09). Surprisingly, combinatorial treatment with STX4 and T09 resulted in an additive effect on reporter-gene activation and target gene expression. In physiological tests the cellular content of total and esterified cholesterol was significantly reduced by STX4 without the undesirable increase in triglyceride levels as observed for T09.
  
  
  CONCLUSIONS
  STX4 is a new LXRα-ligand to study transcriptional regulation of anti-atherogenic processes in cell or ex vivo models, and provides a promising lead structure for pharmaceutical development.
authors: Otto Warburg Laboratory, Max Planck Institute for Molecular Genetics, Berlin, Germany.
authors: Radmila
authors: R
authors: Feldmann
authors: Anne
authors: A
authors: Geikowski
authors: Christopher
authors: C
authors: Weidner
authors: Annabell
authors: A
authors: Witzke
authors: Vitam
authors: V
authors: Kodelja
authors: Thomas
authors: T
authors: Schwarz
authors: Mario
authors: M
authors: Gabriel
authors: Thomas
authors: T
authors: Erker
authors: Sascha
authors: S
authors: Sauer
mesh_terms: D002460:Cell Line; D005487:Foam Cells / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D006801:Humans; D008024:Ligands; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors / Q000235:genetics / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D008024:Ligands; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; D057093:Orphan Nuclear Receptors