Kuwanons G and K, Constitutional Isomers of Plant Flavonoids, Are LXR Ligands with Distinct Agonist and Inverse Agonist Cellular Activities

Abstract Liver X receptors (LXRα/β) are members of the nuclear receptor superfamily that have garnered attention over the last two decades. LXRα/β regulate myriad biological functions, including metabolism, cholesterol homeostasis, and immune responses, suggesting they may be effective drug targets for a range of diseases. Kuwanon G, a botanical-origin flavonoid, has previously been shown to regulate LXR-driven biological pathways, but the exact target of this compound has not been fully demonstrated. We conducted LXRα/β radioligand-binding and co-transfection reporter assays, as well as direct examination of LXRα/β target gene expression in HepG2 cells. Kuwanon G displayed potent LXRα binding activity as well as agonist activity in cell-based assays. Based on the activity of kuwanon G, we also examined other kuwanons with relevant structures (kuwanon C and kuwanon K). While kuwanon C showed insignificant activity in the radioligand binding assay, kuwanon K, a constitutional isomer of kuwanon G, displayed high-affinity binding to LXRα/β, but intriguingly, kuwanon K functioned as an LXRα/β inverse agonist in the cotransfection and gene expression assays. This study provides critical structural insights into the chemical diversity that drives agonism vs inverse agonism as essential knowledge for opportunities in LXRα/β ligands from botanical sources.