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Articles in PresS, published online ahead of print October 31, 2001
Am J Physiol Gastrointest Liver Physiol, 10.1152/ajpgi.00371.2001
Submitted on August 20, 2001
Accepted on October 29, 2001
1 Membrane Biology Program and Renal Division, Harvard Medical School, Brigham & Women's Hospital, Boston, MA, USA; The Liver-Biliary-Pancreatic Center, University of Massachusetts Medical School, Worcester, MA, USA
2 The Liver-Biliary-Pancreatic Center, University of Massachusetts Medical School, Worcester, MA, USA
3 The Liver-Biliary-Pancreatic Center, University of Massachusetts Medical School, Worcester, MA, USA; Division of Gastroenterology, Albany Medical College, Albany, NY, USA
4 Membrane Biology Program and Renal Division, Harvard Medical School, Brigham & Women's Hospital, Boston, MA, USA
* To whom correspondence should be addressed. E-mail: arolfs{at}rics.bwh.harvard.edu.
Hereditary hemochromatosis (HHC) is one of the most frequent genetic disorders in humans. It is caused by a missense mutation (C282Y) in the HFE gene which triggers excessive intestinal iron absorption, followed by toxic accumulation of iron in the liver and other organs. In healthy individuals, the absorption of iron in the intestine is tightly regulated by the cells with highest iron demand, in particular erythroid precursors. The cloning of the intestinal iron transporter proteins, DCT1 and IREG1/hephaestin, provided new insight into the mechanisms and regulation of intestinal iron absorption. The aim of this study was to assess whether, in man, the two transporters are regulated in an iron dependent manner, and whether this regulation is disturbed in HHC. Using quantitative PCR, we measured the RNA expression of DCT1, IREG, and hephaestin mRNA expression in duodenal biopsy samples of individuals with normal iron levels, iron deficiency anemia, or iron overload due to liver disease or hereditary hemochromatosis. In control subjects, we found inverse relationships between the DCT1 splice form containing an iron-responsive element (IRE), and blood hemoglobin, serum transferrin saturation, or ferritin. Subjects with iron-deficiency anemia show a significant increase in expression of DCT1(IRE) mRNA when compared with controls. Similarly in subjects homozygous for the C282Y HFE mutation, the DCT1(IRE) expression levels remained high, despite high serum iron saturation. In HHC, we found a significantly increased IREG1 expression, compared with controls. Hephaestin did not exhibit a similar iron dependent regulation. In conclusion, our data show that the expression of the human DCT1 mRNAs is regulated in an iron-dependent manner, similar to other mammals, while the mRNA of hephaestin is not affected. In HHC patients, the mRNA expression levels of DCT1 and IREG1 remain high despite elevated serum transferrin saturation and ferritin levels. The lack of appropriate down regulation of the apical and basolateral iron transporter in duodenum leads to excessive iron absorption in persons with HHC.
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