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. Methods and 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