Absorption, storage, and transport: Intestinal uptake of heme is by a heme carrier protein (Fig. 29.8). Within the enterocytes, heme oxygenase releases Fe2+ from heme (see p. 282). Nonheme Fe is taken up via the apical membrane protein divalent metal ion transporter-1 (DMT-1). [Note: Vitamin C enhances absorption of nonheme Fe because it is the coenzyme for duodenal cytochrome b (Dcytb), a ferrireductase that reduces Fe3+ to Fe2+.] Absorbed Fe2+ from heme and nonheme sources has two possible fates: It can be 1) oxidized to Fe3+ and stored by the intracellular protein ferritin (up to 4,500 Fe3+/ferritin) or 2) transported out of the enterocyte by the basolateral membrane protein ferroportin, oxidized by the Cu-containing membrane protein hephaestin, and taken up by the plasma transport protein transferrin (2 Fe3+/transferrin), as shown in Figure 29.8. [Note: Cells other than enterocytes use the Cu-containing plasma protein ceruloplasmin in place of hephaestin.] In normal individuals, transferrin (Tf) is about one third saturated with Fe3+ . Ferroportin, the only known exporter of Fe from cells to the blood in humans, is regulated by the hepatic peptide hepcidin that induces internalization and lysosomal degradation of ferroportin. Therefore, hepcidin is the central molecule in Fe homeostasis. [Note: Transcription of hepcidin is suppressed when Fe is deficient.] 2.
Recycling: Macrophages phagocytose old and/or damaged red blood cells (RBC), freeing heme Fe that is sent out of the cells via ferroportin, oxidized by ceruloplasmin, and transported by Tf as described above. This recycled Fe meets ~90% of our daily need, which is predominantly for erythropoiesis.
3.
Uptake: Tf-bound Fe3+ from enterocytes and macrophages binds to receptors (TfR) on erythroblasts and other Fe-requiring cells and is taken up by receptor-mediated endocytosis. The Fe3+ is released from Tf for use (or stored on ferritin), and the TfR (and Tf) is recycled in a process similar to the receptor-mediated endocytosis seen with low-density lipoprotein particles (see p. 231). [Note: Regulation of the translation of the messenger RNA for ferritin and the TfR by iron regulatory proteins and iron-responsive elements is discussed on p. 474.] 4.
Deficiency: Fe deficiency can result in a microcytic, hypochromic anemia (Fig. 29.9), the most common anemia in the United States, as a result of decreased hemoglobin synthesis and, consequently, decreased
RBC size. Treatment is the administration of Fe.