A hypothetical model for iron absorption was developed from discovery of three 'new' iron binding proteins in rat and human duodenal mucosa. Mucins bind iron at the acid pH of the stomach to keep it soluble and available for absorption at the more alkaline pH of the duodenum. Intern (90/150 kD) - a member of a superfamily of transmembrane proteins - was identified in duodenal microvilli in association with radioiron and is believed to facilitate transport of iron into the cell. Mobilferrin is a 56 kD cytosol protein which binds iron and other metal cations and is a homologue of calreticulin. It coprecipitates with integrin and occurs in close association with it in the absorptive cells. This suggests mobilferrin accepts iron from integrin and acts as the shuttle protein for iron in cellular cytosol. Since iron in intestinal cells remains in equilibrium with body stores, we postulate mucosal iron uptake is regulated by the number of iron binding sites occupied by iron or another competitive metal on mobilferrin. The mucosal cell is probably informed of body requirements for iron by transfer of iron from plasma via the transferrin receptor pathway localized to the basolateral membranes of the absorptive cell; this is similar to the iron delivery system in other cells. While the method for transfer of mucosal iron into plasma is not defined, we postulate it occurs via integrin on the basal surface of the cell and the absorptive process is driven by a cascade of differences in binding constants so that iron move from luminal mucin to mucosal mobilferrin to plasma transferrin. Preliminary data showing mobilferrin and integrin radiolabeled in non intestinal cells suggests this may explain the non transferrin receptor mediated uptake of iron reported by others in cells from other body organs. Further, the non transferrin pathway for iron absorption appears to be shared with other metal cations of biological importance (Zn, Ca, Mn, Ni, Pb). Integrins involved in metal transport across cell membranes will be characterized and the interaction between mobilferrin and integrin delineated. Tissue culture systems of both intestinal and non intestinal origin will be employed to delineate the regulation of the mobilferrin-integrin system. In vivo studies will be performed in rats under conditions known to affect iron absorption in which mobilferrin and integrin will be quantified by biochemical, immunological and functional methods to determine their respective roles in the regulation of iron absorption. Heme iron uptake will be investigated in an intestinal tissue culture to investigate similarities and differences in the absorption of inorganic iron. These studies should provide a basic understanding of the cellular transport of iron and other metal cations.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Method to Extend Research in Time (MERIT) Award (R37)
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Hematology Subcommittee 2 (HEM)
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University of South Alabama
Internal Medicine/Medicine
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United States
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Simovich, Marcia; Hainsworth, Lucille N; Fields, P A et al. (2003) Localization of the iron transport proteins Mobilferrin and DMT-1 in the duodenum: the surprising role of mucin. Am J Hematol 74:32-45
Umbreit, Jay N; Conrad, Marcel E; Hainsworth, Lucille N et al. (2002) The ferrireductase paraferritin contains divalent metal transporter as well as mobilferrin. Am J Physiol Gastrointest Liver Physiol 282:G534-9
Simovich, Marcia J; Conrad, Marcel E; Umbreit, Jay N et al. (2002) Cellular location of proteins related to iron absorption and transport. Am J Hematol 69:164-70
Conrad, Marcel E; Umbreit, Jay N (2002) Pathways of iron absorption. Blood Cells Mol Dis 29:336-55
Conrad, M E; Umbreit, J N; Moore, E G et al. (2000) Separate pathways for cellular uptake of ferric and ferrous iron. Am J Physiol Gastrointest Liver Physiol 279:G767-74
Barber, M; Conrad, M E; Umbreit, J N et al. (2000) Abnormalities of flavin monooxygenase as an etiology for sideroblastic anemia. Am J Hematol 65:149-53
Conrad, M E; Umbreit, J N (2000) Iron absorption and transport-an update. Am J Hematol 64:287-98
Conrad, M E (1998) Introduction: iron overloading disorders and iron regulation. Semin Hematol 35:1-4
Uzel, C; Conrad, M E (1998) Absorption of heme iron. Semin Hematol 35:27-34
Umbreit, J N; Conrad, M E; Moore, E G et al. (1998) Iron absorption and cellular transport: the mobilferrin/paraferritin paradigm. Semin Hematol 35:13-26

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