Regulation of Intestinal Iron Absorption: Balancing Supply and Demand

Iron, an essential micronutrient, is involved in several physiological activities, including oxygen transport, cellular respiration, and DNA synthesis. Its homeostasis is strictly controlled to avoid overload and deficiency. Ferrous iron is taken up by intestinal enterocytes through the apical membrane with the help of divalent metal transporter 1 (DMT1). Iron can then be discharged into the bloodstream by ferroportin 1 (FPN1) or stored intracellularly in ferritin. Hepcidin, a hormone produced in the liver, binds to FPN1 and causes its internalization and degradation, a key factor in controlling systemic iron levels. Thus, hepcidin limits the absorption and release of iron by decreasing the iron outflow from enterocytes and macrophages. Iron-responsive element/iron regulatory protein (IRE/IRP) system and hypoxia-inducible factor 2 (HIF-2) are important cellular regulators of iron homeostasis. The IRE/IRP system post-transcriptionally regulates the expression of iron-related proteins in response to iron availability. At the same time, HIF-2 promotes the expression of iron transporters and metabolic enzymes under hypoxic conditions. Iron-related disorders can result from disruptions in these regulatory mechanisms; for instance, mutations in the genes encoding hepcidin, FPN1, or hereditary hemochromatosis protein (HFE) can cause iron overload disorders like hemochromatosis, while iron deficiency anemia is caused by impaired iron absorption due to genetic defects or nutritional deficiencies. A deeper understanding of these intricate mechanisms is crucial for developing effective strategies to prevent and treat iron-related disorders.