HFE downregulates iron uptake from transferrin and induces iron-regulatoryprotein activity in stably transfected cells

Hereditary hemochromatosis (HH) is a common autosomal-recessive disorder of iron metabolism. More than 80% of HH patients are homozygous for a point m utation in a major histocompatibility complex (MHC) class I type protein (H FE). which results in a lack of HFE expression on the cell surface. A previ ously identified interaction of HFE and the transferrin receptor suggests a possible regulatory role of HFE in cellular iron absorption. Using an HeLa cell line stably transfected with HFE under the control of a tetracycline- sensitive promoter, we investigated the effect of HFE expression on cellula r iron uptake. We demonstrate that the overproduction of HFE results in dec reased iron uptake from diferric transferrin. Moreover, HFE expression acti vates the key regulators of intracellular iron homeostasis, the iron-regula tory proteins (IRPs), implying that HFE can affect the intracellular "labil e iron pool." The increase in IRP activity is accompanied by the downregula tion of the iron-storage protein, ferritin, and an upregulation of transfer rin receptor levels. These findings are discussed in the context of the pat hophysiology of HH and a possible role of iron-responsive element (IRE)-con taining mRNAs. (C) 1999 by The American Society of Hematology.