Cid

Ireg1

Figure 3 Absorption of iron in the intestinal mucosa.

Duodenal lumen

Regulation of Iron Absorption

Differentiating mucosal crypt cells

Plasma

Cellular Fe status influences IRP-IRE system, regulating DNA expression of DMT-1, ferritin, Tfr1 Dcytb(?) IREG(?)

Plasma

Cellular Fe status influences IRP-IRE system, regulating DNA expression of DMT-1, ferritin, Tfr1 Dcytb(?) IREG(?)

Fe C

^ Hepcidin?

Fe C

^ Hepcidin?

Figure 4 Regulation of iron absorption in the mucosal crypt cells before differentiation and development into actively absorbing intestinal villi cells.

accumulation of iron in intestinal cells. However, unlike Dcytb, DMT-1, or Ireg-1, hephaestin is not preferentially expressed in the duodenum, the main site of iron absorption.

Iron absorption is responsive to recent iron intake, iron stores, erythropoiesis, hypoxia, pregnancy, and inflammation. A newly identified peptide, hepcidin, may be related to several of these stimuli of regulatory control. Hepcidin is an antimicrobial peptide found in human blood and urine that apparently serves as a signal for limiting iron absorption. Control of absorption also likely involves the HFE protein located in the basolateral membrane of intestinal crypt cells. A specific point mutation in the HFE gene is associated with the most common form of hemochromatosis, a disorder involving excessive iron absorption and accumulation. The HFE protein interacts with ,32-microglobin and transferrin receptor, apparently influencing iron uptake from serum transferrin, the primary protein involved in serum iron transport (Figure 4). Knowledge of the control of iron absorption is growing rapidly.

Transport Transferrin transports essentially all of the 3 or 4mg of iron in blood serum, including dietary iron absorbed from the duodenum as well as iron from macrophages after the degradation of hemoglobin. Each transferrin molecule binds two iron atoms; the transferrin in serum is normally approximately one-third saturated with iron. The amount of iron that can be bound by transferrin is measured as the total iron binding capacity (TIBC). In iron deficiency, serum iron is reduced, and TIBC is elevated; expressing serum iron as a fraction of the TIBC defines the transferrin saturation, which is reduced in iron deficiency. As iron deficiency develops, these measures of iron transport signal iron deficiency before the functional pool of circulating hemoglobin is reduced (Figure 5).

Membrane transferrin receptors enable the cellular uptake of iron. Transferrin receptors complex with transferrin, the complex is internalized by endocytosis, and the iron is released to the cell from transferrin upon vesicular acidification (Figure 4). Transferrin receptors are abundant in erythrocyte precursors, placenta, and liver, and the number of receptors changes inversely with cellular iron status. Serum transferrin receptors are a soluble, truncated form of the cellular receptors, present in proportion to the cellular receptors, which serve as a clinical indicator of cellular iron status that is useful in distinguishing between iron deficiency and other causes of anemia.

Other proteins involved in iron transport include lactoferrin, which is structurally similar to transfer-rin and occurs in body fluids such as milk and semen. Haptoglobin and hemopexin proteins clear hemoglobin and heme, respectively, from circulation as they are released from senescent red blood cells.

Storage Iron is primarily stored in liver, spleen, and bone marrow in the form of ferritin or hemo-siderin. Ferritin is a water-soluble protein complex of 24 polypeptide subunits in a spherical cluster with a hollow center that contains up to 25% iron by weight, or 4000 atoms of iron per molecule.

I Iron Excess Iron Depletion

I Iron Excess Iron Depletion

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