The effects of quercetin on iron metabolism

Polyphenols are known to be major inhibitors of dietary non-haem iron bioavailability, mainly through their action as iron chelators. In this present study Caco-2 cells were used to investigate the influence of quercetin, the most abundant flavonol in the diet, on non-haem iron bioavailability using 55Fe, and the gene expression of intestinal iron transporters as measured via qPCR. Chronic exposure to quercetin (24 hours) had no significant effect on iron uptake but iron efflux was significantly decreased. Consistent with this, qPCR analysis revealed a significant decrease in basolateral transport genes ferroportin (FPN) and hephaestin expression suggesting polyphenols may have direct gene regulatory effects. Exploring the cellular mechanisms underlying quercetin-induced FPN down-regulation, transfection of 5’FPN promoter constructs showed quercetin did not affect activity but did decrease FPN1A mRNA whilst increasing FPN1B expression; this suggests that although FPN1B is specific to intestinal epithelial cells, FPN1A remains the major isoform. FPN 3’UTR miRNA array analysis identified candidate hsa-miR-17-3p to be significantly activated by quercetin (1.5 fold) and qPCR validation confirmed up-regulation of 101 ± 25.1 -fold (p<0.01). This represents a novel mechanism of quercetin-induced miRNA-mediated regulation of FPN. In HepG2 cells quercetin stimulated hepcidin expression and inhibited ferroportin gene expression; this may provide an additional means of regulating systemic iron levels. Quercetin was shown to be both pro- and anti- proliferative/apoptotic dependent on the concentration used which may have beneficial consequences for liver pathology of iron-overload diseases. In contrast to findings in Caco-2 cells, in Thp1 macrophages quercetin caused a significant dose-dependent increase in FPN expression. Furthermore, quercetin induced both FPN1A and 1B promoter activities. This strongly implies that quercetin acts at the level of the FPN promoter to increase FPN expression - an effect specific to macrophages only. This demonstrates that quercetin has cell-specific effects and its actions on FPN are differentially regulated dependent on cell/tissue type. The results show that quercetin can have multiple effects on iron homeostasis. Given its relatively long half-life in the circulation, repeated dietary intake of quercetin could lead to plasma accumulation in vivo. This may have important consequences for conditions that are low in iron such as anaemia; alternatively it has therapeutic potential for iron overload diseases such as haemochromatosis. By deducing the mechanisms of how dietary polyphenols interact with our intake of essential nutrients such as iron, intake can be optimised to harness the potential benefits polyphenols have to offer.