Intestinal absorption of iron and manganese in Hfe knockout mice

Abstract

HFE gene mutations are the most common cause of hereditary hemochromatosis. This inherited form of iron overload is due to excessive dietary iron absorption. Loss of HFE function is associated with reduced expression of hepcidin in response to iron loading. This peptide hormone regulates levels of ferroportin, a transporter responsible for iron export across the duodenum. High levels of ferroportin are thought to promote high intestinal iron uptake in hemochromatosis. Recently, it has been proposed that ferroportin may mediate transport of other metals, including manganese, but physiological roles of HFE and ferroportin in intestinal manganese absorption have not been tested. To investigate whether loss of HFE function alters metal absorption, we characterized the pharmacokinetics of iron and manganese in Hfe−/− mice. While Hfe−/− mice displayed higher serum and liver iron, manganese blood levels were not greater than Hfe+/+ mice. Hfe−/− mice showed elevated blood appearance and enhanced tissue distribution of 59Fe after intragastric gavage, and blood 59Fe clearance was accelerated following intravenous injection. In contrast, 54Mn pharmacokinetics were unchanged in Hfe−/− mice following either route of administration. These data suggest HFE modifies intestinal uptake of iron but not manganese in mice. Supported by NIH R03 DA027030 and K99 ES017781.