The Gut: Role at Steady State and Variations in Disordered Conditions

Abstract SCI-23

As the human body cannot excrete excess iron, its absorption needs to be finely regulated at the intestinal level. Ferric iron (Fe³⁺) is reduced to ferrous iron (Fe²⁺) by brush border ferric reductases, including duodenal cytochrome b (DCYTB), before being transported across the apical membrane by divalent metal transporter 1 (DMT1), which is the principal iron importer. Depending on body iron requirements, iron can be either stored bound to ferritin or exported across the basolateral enterocyte membrane into the plasma by the sole iron exporter ferroportin (FPN). Iron absorption responds to systemic signals reflecting body iron requirements and local signals in the enterocyte. At the systemic level, hepcidin is the key circulating peptide hormone maintaining iron homeostasis. Hepcidin controls plasma iron concentration by inhibiting intestinal iron absorption and iron recycling by macrophages. Hepcidin acts by inhibiting cellular iron efflux through binding to and inducing the degradation of FPN. Hepcidin transcription is upregulated by iron repletion and downregulated by iron deficiency, ineffective erythropoiesis, and hypoxia. Hypoxia-inducible factors HIF-1 and HIF-2 are heterodimeric transcriptional factors and central mediators of cellular and systemic adaptation to hypoxia. In the presence of oxygen, the HIF-α subunit is targeted to the proteasome, while in hypoxia (or iron deficiency), HIF-α is stabilized and induces the transcription of target genes. We hypothesized that HIFs, stabilized in the hypoxic intestinal epithelium, may also play critical local roles in regulating intestinal iron absorption. We generated conditional knockout mice that lacked either Hif1a or Hif2a specifically in the intestinal epithelium and found that HIF-1α was not necessary for iron absorption, whereas HIF-2α played a crucial role in maintaining iron balance in the organism by directly regulating the transcription of the genes encoding DMT1 and DCYTB. Specific deletion of Hif2a led to a decrease in serum and liver iron levels. Alterations in HIF-2 at the intestinal level can override systemic regulation via hepcidin. Interestingly, we further demonstrated that HIF-2α contributes to iron hyperabsorption in a genetic mouse model of hereditary hemochromatosis (HH). HH is a genetic disorder characterized by abnormally low hepcidin expression and excessive iron accumulation in the liver and parenchyma. These findings suggest a prominent role of HIF-2 in the physiopathological regulation of intestinal iron absorption and may provide new therapeutic perspectives for the treatment of anemias and iron overload-associated disorders.