Date Published: July 13, 2017
Publisher: Public Library of Science
Author(s): Robert Staroń, Paweł Lipiński, Małgorzata Lenartowicz, Aleksandra Bednarz, Anna Gajowiak, Ewa Smuda, Wojciech Krzeptowski, Marek Pieszka, Tamara Korolonek, Iqbal Hamza, Dorine W. Swinkels, Rachel P. L. Van Swelm, Rafał R. Starzyński, Kostas Pantopoulos.
Heme is an efficient source of iron in the diet, and heme preparations are used to prevent and cure iron deficiency anemia in humans and animals. However, the molecular mechanisms responsible for heme absorption remain only partially characterized. Here, we employed young iron-deficient piglets as a convenient animal model to determine the efficacy of oral heme iron supplementation and investigate the pathways of heme iron absorption. The use of bovine hemoglobin as a dietary source of heme iron was found to efficiently counteract the development of iron deficiency anemia in piglets, although it did not fully rebalance their iron status. Our results revealed a concerted increase in the expression of genes responsible for apical and basolateral heme transport in the duodenum of piglets fed a heme-enriched diet. In these animals the catalytic activity of heme oxygenase 1 contributed to the release of elemental iron from the protoporphyrin ring of heme within enterocytes, which may then be transported by the strongly expressed ferroportin across the basolateral membrane to the circulation. We hypothesize that the well-recognized high bioavailability of heme iron may depend on a split pathway mediating the transport of heme-derived elemental iron and intact heme from the interior of duodenal enterocytes to the bloodstream.
Heme, a ferrous iron protoporphyin IX complex, is employed as a prosthetic group in diverse proteins that participate in important biological processes . The provision of an adequate amount of iron for heme biosynthesis is essential for intracellular iron homeostasis. Likewise, the delivery of iron for heme/hemoglobin synthesis in erythroblasts is indispensable for maintenance of the body iron balance. These processes rely on the recovery of iron from senescent erythrocytes, through the circulation. Molecular coordination of these activities involves the functions of heme oxygenase 1 (HO1), an inducible heme-degrading enzyme , the post-transcriptional IRE/IRP system , as well as the hepcidin-ferroportin regulatory axis . Interestingly, recent mammalian studies have demonstrated the existence of an expanded system of proteins involved in the transport of intact heme across biological membranes [5–8]. Heme exported to the bloodstream is scavenged by hemopexin (Hpx), an effective heme-binding protein found in blood plasma, which acts primarily to deliver heme to cells via CD91 receptor-mediated endocytosis [9,10]. This system is of particular importance when the concentration of free heme reaches toxic levels in the body  or locally in cells with an intensive heme metabolism . On the other hand, there is growing evidence that the movement of intact heme molecules takes place under physiological conditions and constitutes an integral part of iron turnover in the body . It has long been known that exogenous heme can be efficiently taken up by enterocytes as an intact metalloporphyrin molecule via receptor-mediated endocytosis, and thus may provide a highly bioavailable source of dietary iron for the organism [13–15]. Although recent studies have led to the identification of intestinal heme transporters [16,17], the molecular mechanisms of dietary heme absorption remain the subject of some controversy [15,18] and our understanding of this process is far from complete.
Dietary heme uptake by enterocytes has been recognized for more than 60 years . Many studies over these decades have since confirmed that absorption of heme is far more efficient than that of inorganic iron [13,34]. However, our understanding of the molecular mechanisms of heme iron absorption remains poor. Recent mammalian studies have demonstrated several proteins involved in the transport of intact heme molecules at both the cellular and systemic levels [5–7,35]. Absorption of intact heme molecules by enterocytes might also contribute to systemic heme turnover under physiological conditions. Indeed, the recent discovery of a heme transporter that may transfer heme from the duodenum lumen directly into the enterocytes  and from enterocytes into the circulation , suggests a new putative pathway for trafficking intact heme across the enterocyte. Despite our limited knowledge of the molecular mechanisms of dietary absorption, heme preparations are successfully used to prevent and cure iron deficiency anemia in humans [12,14,31,36], dogs , and pigs .