Transferrin Receptor 1 (TfR1) and Putative Stimulator of Fe Transport (SFT) Expression in Iron Deficiency and Overload: An Overview Submitted 10/3/02 (Communicated by E. Beutler, M.D., 10/15/02 Donatella Barisani 1 and Dario Conte 2 ABSTRACT: Transferrin Receptor 1 (TfR1) and putative Stimulator of Fe Transport (SFT) represent two different proteins involved in iron metabolism in mammalian cells. The expression of TfR1 in the duodenum of subjects with normal body iron stores has been mainly localized in the basolateral portion of the cytoplasm of crypt cells, supporting the idea that this molecule may be involved in the sensing of body iron stores. In iron deficiency anemia TfR1 expression demonstrated an inverse relationship with body iron stores as assessed by immunohis- tochemistry with anti-TfR1 antibodies. In iron overload, TfR1 expression in the duodenum differed according to the presence or absence of the C282Y mutation in the HFE gene, being increased in HFE-related hemochromatosis and similar to controls in non-HFE-related iron overload. SFT is characterized by its ability to increase iron transport both through the transferrin dependent and independent uptake, and could thus affect iron absorption in the intestine. Immunohistochemistry using anti-SFT antibodies which recognize a putative stimulator of Fe transport of 80 KDa revealed a localization of this protein in the apical part of the cytoplasm of enterocytes localized at the tip of the villi. The expression of the protein recognized by these antibodies was increased in iron deficiency, as well as in patients carrying the C282Y HFE mutation. Thus, the increased expression of both proteins only in patients with HFE-related hemochromatosis suggests that other factors should be involved in determining non-HFE-related iron overload. © 2002 Elsevier Science (USA) INTRODUCTION An excess of intracellular iron may be toxic through the generation of highly reactive hy- droxyl radicals which can generate lipid peroxi- dation (1), organelle dysfunction, and eventu- ally cell death [reviewed in 2]. Thus a close regulation of iron metabolism, mainly obtained by controlling the expression of the genes di- rectly involved in iron uptake and storage, is mandatory. In a normal adult individual, body iron stores amount to about 3–5 g, two thirds of which are incorporated into hemoglobin in developing ery- throid precursors and mature red cells. Most of the remaining body iron, 0.5 to 1 g, is found in hepatocytes that store the metal into specialized proteins such as ferritin and hemosiderin. Pro- cesses such as sloughing of skin and menstruation cause a daily body iron loss of 1–2 mg of iron, amount which is replaced by the absorption of dietary iron that occurs through the mucosa of the duodenum. Intestinal iron absorption includes uptake across the apical membrane via an energy- dependent and carrier-mediated process (3), that represents the rate-limiting step for iron absorption (4). The protein responsible for the intestinal uptake of non-heme iron is DMT1, previously named Divalent Cation Transporter DCT1 (5) or Nramp2 (6). DMT1 is a highly hydrophobic integral membrane glycoprotein Correspondence and reprint requests to: Donatella Barisani, M.D., Dept. Of Experimental and Environmental Medicine and Medical Biotechnology, University of Milano Bicocca, Via Cadore 48, 20052 Monza, Italy. Fax: ++39-02-64488450. E-mail: donatella.barisani@unimib.it. 1 Department Of Experimental and Environmental Medicine and Medical Biotechnology, University of Milano Bicocca, Monza, Italy. 2 Cattedra di Gastroenterologia, IRCCS Ospedale Maggiore, Milan, Italy. Blood Cells, Molecules, and Diseases (2002) 29(3) Nov/Dec: 498 –505 Barisani and Conte doi:10.1006/bcmd.2002.0588 1079-9796/02 $35.00 © 2002 Elsevier Science (USA) All rights reserved. 498