A model for the establishment of the enterocyte iron absorptive set point in the crypt.

Precursor cells (left) present in duodenal crypts express a complement of iron metabolic proteins that are distinct from those of the differentiated enterocyte (right). In the crypt, the transferrin receptor (TfR)–HFE complex facilitates iron uptake from transferrin (Tf) in the plasma and contributes to the labile iron pool. The labile iron pool directly influences iron regulatory protein RNA binding activity and may affect iron-regulated transcription, translation, protein trafficking, and degradation processes. In this way, the iron absorptive capacity, or set point for the enterocyte, may be established in the crypt. When the precursor cell differentiates, the expression of proteins specific to the enterocyte, such as the apical and basolateral iron transporters and hephaestin, is induced. Although the enterocyte precursor absorbs, but does not transport iron, the differentiated enterocyte takes up iron from the duodenum at the apical membrane through the divalent metal transporter (DMT1) and transports it into the plasma. The basolateral iron transporter, Ferroportin1/Ireg1/MTP1 (F/I/M), has been shown to act independently as an iron exporter. The multicopper oxidase, hephaestin, is also required for efficient iron efflux from the enterocyte, but whether it acts through Ferroportin1/Ireg1/MTP1 or another pathway is not yet known.