A model for local and systemic control of intestinal iron transport. (A) Low dietary iron and systemic iron deficiency lead to up-regulation of DMT1 protein levels, which increases the capacity of the enterocyte for dietary iron uptake. Similarly, increased Ireg1 and Hephaestin protein expression increases the capacity of the enterocyte for the transit of iron to plasma. (B) Low dietary iron with sufficient systemic iron stores leads to increased DMT1 expression, whereas Ireg1 and Hephaestin protein levels are decreased, which may represent a muscosal block to iron absorption. (C) High dietary iron and sufficient iron stores result in decreased levels of DMT1, Ireg1, and Hephaestin protein and minimal iron absorption. (D) In enterocytes from the sla mouse, impaired basolateral transport due to a defect in Hephaestin leads to iron accumulation. Iron accumulation in sla enterocytes leads to decreased uptake of dietary iron through decreased DMT1 mRNA and protein levels. Despite intracellular iron accumulation, Ireg1 mRNA and protein levels are increased, likely in response to systemic signals of iron deficiency.