Effects of polyphenols on nuclear receptor activation and their role in modulating inflammation

Polyphenols are associated with numerous biological activities and health benefits for human health. However, the exact mechanism of how polyphenols act on a cellular level is not well known. It has recently been suggested that some members of the flavonoid subgroup of polyphenols might have the ability to act as ligands for nuclear receptors and thereby impact on transcriptional regulation of metabolic pathways, such as cell development, energy metabolism, and inflammation. Meanwhile, LXRα is a ligand-dependent nuclear receptor that plays an important role in the control of lipid and cholesterol metabolism, as well as inflammatory disease making LXRα an interesting target. Therefore, this project aimed to assess the role of LXRα in the anti-inflammatory properties of polyphenols. Representatives of each polyphenol class were tested for their ability to act as a ligand for LXRα in MDA-MB-231 stably transfected with LXRα target gene as the cell model, followed by the evaluation of LXRα target genes modulation in vitro.
Quercetin appears to have the potency as a partial agonist of LXRα by showing the ability to modulate LXRα activity on both MDA-MB-231 and HepG2 cell lines. This study demonstrated that there is a structure-function relationship between polyphenol and ligand-activated function of LXRα as shown by the ability of tamarixetin but not isorhamnetin, both methylated form metabolites of quercetin, to induce the activity of LXRα. Furthermore, in the hepatic inflammation model, quercetin, tamarixetin, and GW3965 as LXRα ligand, failed to suppress inflammatory cytokine production following TNF-α induced inflammation.
Meanwhile, GW3965 and quercetin showed anti-inflammatory activities in RAW264.7 macrophages. Both compounds inhibit inflammation by interfering with the NF-κB signaling pathway and inhibit pro-inflammatory cytokines production. The anti-inflammatory properties of quercetin are independent of LXRα. This study showed that LXRα is partially involved in the anti-inflammatory property of quercetin. Moreover, the ability of quercetin to suppress inflammation is not dependent on ABCA1/LXRα pathway. More studies are needed to understand the relationship between polyphenol structure and nuclear receptor activation and its biological function.