Dataset Information

Foam cell specific LXR? ligand.

ABSTRACT:

Objective

The liver X receptor ? (LXR?) 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 LXR? reporter-gene assays. STX4 displayed the unique property to activate LXR? effectively but not its subtype LXR?. The potential of STX4 to increase transcriptional activity as an LXR? 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 LXR?-ligand to study transcriptional regulation of anti-atherogenic processes in cell or ex vivo models, and provides a promising lead structure for pharmaceutical development.

SUBMITTER: Feldmann R

PROVIDER: S-EPMC3581588 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Publications

Foam cell specific LXRα ligand.

Feldmann Radmila R Geikowski Anne A Weidner Christopher C Witzke Annabell A Kodelja Vitam V Schwarz Thomas T Gabriel Mario M Erker Thomas T Sauer Sascha S

PloS one 20130225 2

<h4>Objective</h4>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.<h4>Methods and results</h4>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 L ...[more]

PMID: 23451202

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