Iron Regulatory Proteins Control a Mucosal Block to Intestinal Iron Absorption

SummaryMammalian iron metabolism is regulated systemically by the hormone hepcidin and cellularly by iron regulatory proteins (IRPs) that orchestrate a posttranscriptional regulatory network. Through ligand-inducible genetic ablation of both IRPs in the gut epithelium of adult mice, we demonstrate that IRP deficiency impairs iron absorption and promotes mucosal iron retention via a ferritin-mediated “mucosal block.” We show that IRP deficiency does not interfere with intestinal sensing of body iron loading and erythropoietic iron need, but rather alters the basal expression of the iron-absorption machinery. IRPs thus secure sufficient iron transport across absorptive enterocytes by restricting the ferritin “mucosal block” and define a basal set point for iron absorption upon which IRP-independent systemic regulatory inputs are overlaid.

Graphical AbstractFigure optionsDownload full-size imageDownload as PowerPoint slideHighlights► Disruption of intestinal IRP function constrains iron absorption in adult mice ► IRPs must limit mucosal ferritin for efficient iron absorption ► IRPs control ferroportin directly and DMT1 directly or through HIF2α ► IRPs define a set point for hepcidin-mediated regulation of iron absorption