HFE inhibits apical iron uptake by intestinal epithelial (Caco‐2) cells

Hereditary hemochromatosis (HH) is a common autosomal recessive disorder of iron metabolism characterized by increased intestinal iron absorption, which leads to progressive iron overload. The protein product of C282Y, the main mutation observed in HH, has lost the capacity to associate with β 2 ‐microglobulin, preventing its targeting to the plasma membrane. The physiological mechanisms by which HFE, the normal product of the HH gene, regulates intestinal iron absorption are unknown. Under the hypothesis that HFE regulates intestinal iron absorption, we characterized the effect of HFE overexpression on apical iron uptake in intestinal epithelial Caco‐2 cells. We found that the primary effect of HFE overexpression was a marked reduction of apical iron uptake, despite a working iron responsive element/iron regulatory protein system and an eightfold increase in the mass of the iron transporter DMT1. The inhibitory effect of HFE on apical iron uptake reported here provides an explanation for the increased absorption of iron observed in HH, where the normal function of HFE is lost.