Iron uptake from plasma transferrin by the duodenum is impaired in the Hfe knockout mouse

Abstract

Hereditary hemochromatosis (HH) is a disorder of iron metabolism in which enhanced iron absorption of dietary iron causes increased iron accumulation in the liver, heart, and pancreas. Most individuals with HH are homozygous for a C282Y mutation in the HFE gene. The function of HFE protein is unknown, but it is hypothesized that it acts in association with ␤2-microglobulin and transferrin receptor 1 to regulate iron uptake from plasma transferrin by the duodenum, the proposed mechanism by which body iron levels are sensed. The aim of this study was to test this hypothesis by comparing clearance of transferrin-bound iron in Hfe knockout (KO) mice with that observed in C57BL͞6 control mice. The mice were fed either an iron-deficient, control, or iron-loaded diet for 6 weeks to alter body iron status. The mice then were injected i.v. with 59 Fe-transferrin, and blood samples were taken over 2 h to determine the plasma 59 Fe turnover. After 2 h, the mice were killed and the amount of radioactivity in the duodenum, liver, and kidney was measured. In both Hfe KO and C57BL͞6 mice, plasma iron turnover and iron uptake from plasma transferrin by the duodenum, liver, and kidney correlated positively with plasma iron concentration. However, duodenal iron uptake from plasma transferrin was decreased in the Hfe KO mice compared with the control mice. Despite this difference in duodenal uptake, the Hfe KO mice showed no decrease in iron uptake by the liver and kidney or alteration in the plasma iron turnover when compared with C57BL͞6 mice. These data support the hypothesis that HFE regulates duodenal uptake of transferrin-bound iron from plasma, and that this mechanism of sensing body iron status, as reflected in plasma iron levels, is impaired in HH.

Hereditary hemochromatosis: update for 2003

“…Supporting this hypothesis are the observations that there is increased expression of DMT-1 and ferroportin 1 in the duodenum of patients with HFElinked HH [56][57][58]. In addition, HFE-knockout mice models of HH show impaired duodenal uptake of circulating transferrin-bound iron [59] and increased duodenal expression of DMT-1 [60,61] and ferroportin 1 [61] These latter effects are modulated by the genetic background of the mice [61] suggesting the existence of genes that can modulate the phenotype of HFE-related HH.…”

Structural, functional, and tissue distribution analysis of human transferrin receptor-2 by murine monoclonal antibodies and a polyclonal antiserum

“…[23][24][25] In agreement with this view, impaired iron uptake from plasma TF has been reported in a murine model of HFE-related HH. 26 TFR-1 represents a component of the body iron sensor by directly interacting with HFE in the epithelial cells of the crypts. 27 It is still unproved whether TFR-2, expressed by the basolateral membrane of duodenal crypt cells as TFR-1, interacts with HFE to play a role in iron sensing.…”

Localization of the iron transport proteins mobilferrin and DMT‐1 in the duodenum: The surprising role of mucin

“…This is regulated, at least in part, by translational control via a group of iron regulatory proteins and iron regulatory sequences on the mRNA for the transferrin receptor and other proteins. In the intestine the transferrin receptor is on the basolateral side and may function to keep the absorptive cell informed of the iron requirements of the body [6]. The intestinal mucosal absorption cells contain iron in proportion to body iron stores [7,8].…”