Flavonoids differentially modulate liver X receptors activity—Structure-function relationship analysis. Issue 190 (June 2019)

• Record Type: Journal Article
• Authors: Fouache, Allan; Zabaiou, Nada; De Joussineau, Cyrille; Morel, Laurent; Silvente-Poirot, Sandrine; Namsi, Amira; Lizard, Gérard; Poirot, Marc; Makishima, Makoto; Baron, Silvère; Lobaccaro, Jean-Marc A.; Trousson, Amalia
• Is Part Of: Journal of steroid biochemistry and molecular biology. Issue 190(2019)
• Page Start: 173
• Page End: 182
• Publication Date: 2019-06
• Subjects: T09 T0901317 -- NAR naringenin -- QUE quercetin -- API apigenin -- LUT luteolin -- GAL galangin -- CYA cyanidin -- LXRs liver X receptors -- LBD ligand binding domain -- LBP ligand binging pocket; LXR -- Flavonoid -- Galangin -- Quercetin -- Apigenin -- Naringenin; Steroid hormones -- Periodicals; Biochemistry -- Periodicals; Hormones -- Periodicals; Molecular Biology -- Periodicals; Hormones stéroïdes -- Périodiques; Steroid hormones; Periodicals; 572.579
• DOI: 10.1016/j.jsbmb.2019.03.028
• Languages: English
• ISSNs: 0960-0760

Abstract

Graphical abstract: Highlights: Flavonoids modulate LXR transcriptional activity. Quercetin activates both LXRα and LXRβ. Apigenin activates LXRβ. Galangin inhibits both LXRα and LXRβ. Molecular docking identifies specific amino-acids involved in LXR activity. Abstract: 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.