Association of HFE protein with transferrin receptor in crypt enterocytes of human duodenum

In hereditary hemochromatosis (HH), intestinal absorption of dietary iron i s increased, leading to excessive iron accumulation in tissues and resultan t organ damage. The HFE protein, which is defective in HH, normally is expr essed in crypt enterocytes of the duodenum where it has a unique, predomina ntly intracellular localization. In placenta, the HFE protein colocalizes w ith and forms a stable association with the transferrin receptor (TfR), pro viding a link between the HFE protein and iron transport. In the present st udy, we examined the relationship of the HFE protein to the TfR in enterocy tes of the human duodenum and measured the uptake of transferrin-bound iron and ionic iron by isolated crypt and villus enterocytes. Immunocytochemist ry showed that the HFE protein and TfR both are expressed in the crypt ente rocytes. Western blots showed that, as was the case in human placenta, the HFE protein in crypt enterocytes is physically associated with the TfR and with beta(2)-microglobulin. The crypt cell fraction exhibited dramatically higher transferrin-bound iron uptake than villus cells. On the other hand, the villus cells showed 2-3 times higher uptake of ionic iron than crypt ce lls. We propose that the HFE protein modulates the uptake of transferrin-bo und iron from plasma by crypt enterocytes and participates in the mechanism by which the crypt enterocytes sense the level of body iron stores. Impair ment of this function caused by HFE gene mutations in HH could provide a pa radoxical signal in crypt enterocytes that programs the differentiating ent erocytes to absorb more dietary iron when they mature into villus enterocyt es.