Flavonoids differentially modulate liver X receptors activity—Structure-function relationship analysis

Liver X receptors (LXRs) α (NR1H3) and β (NR1H2) are nuclear receptors that have been involved in the regulation of many physiological processes, principally in the control of cholesterol homeostasis, as well as in the control of the cell death and proliferation balance. These receptors are thus promising therapeutic targets in various pathologies such as dyslipidemia, atherosclerosis, diabetes and/or cancers. These receptors are known to be activated by specific oxysterol compounds. The screening for LXR-specific ligands is a challenging process: indeed, these molecules should present a specificity towards each LXR-isoform. Because some natural products have significant effects in the regulation of the LXR-regulated homeostasis and are enriched in flavonoids, we have decided to test in cell culture the effects of 4 selected flavonoids (galangin, quercetin, apigenin and naringenin) on the modulation of LXR activity using double-hybrid experiments. In silico, molecular docking suggests specific binding pattern between agonistic and antagonistic molecules. Altogether, these results allow a better understanding of the ligand binding pocket of LXRα/β. They also improve our knowledge about flavonoid mechanism of action, allowing the selection and development of better LXR selective ligands.