Summary: Nancy Andrews studies mouse models of human diseases, focusing on disorders of iron homeostasis.
Iron balance is critical for normal red blood cell production and general health. Iron deficiency typically presents with anemia, caused by dietary iron insufficiency or ongoing blood loss. It is prevalent throughout the world, particularly among infants, toddlers, and young women. Rarely, iron deficiency results from inherited defects in iron metabolism.
In contrast, hereditary hemochromatosis, a prevalent iron-overload disorder, results from genetic abnormalities in the regulation of dietary iron absorption. It is characterized by pathological deposition of iron, leading to cirrhosis, liver cancer, heart disease, and diabetes. Hemochromatosis is caused by mutations in genes encoding proteins that regulate or carry out intestinal iron absorption.
Progress has been made in understanding iron transport, but relatively little is known about its regulation. We recently turned our focus toward understanding the complex mechanisms involved in maintaining iron homeostasis in vivo.
The Crossing of Cell Membranes by Iron
Iron is a large, charged ion that cannot freely cross lipid-rich cellular membranes. We and others have identified molecules that carry iron into cells (DMT1, for divalent metal transporter 1) and out of cells (ferroportin). Through experiments in mutant mice and rats, we showed that DMT1, which sits on the surface of the intestine that comes in contact with food, is responsible for almost all dietary nonheme iron uptake. We generated mice lacking DMT1 in all tissues and found that they survive for a few days after birth but have severe iron-deficiency anemia. We selectively inactivated DMT1 in individual mouse tissues and proved that, while DMT1 is needed for iron uptake in the intestine, it also plays an important role in bringing iron into red blood cell precursors for hemoglobin biosynthesis. In contrast, DMT1 is not necessary for iron transfer across the placenta or for iron uptake by macrophages or liver cells. (This work was supported by a grant from the National Institutes of Health.)
Ferroportin had been postulated to be important both for moving iron out of intestinal lining cells into the bloodstream and for moving iron out of macrophage cells. The macrophages play a critical role in body iron distribution because they recover used iron from old red blood cells and return it to the circulation. In collaboration with Antonello Pietrangelo (University of Modena, Italy), we showed that some hemochromatosis patients have a defective ferroportin gene.
We generated mice that lack the ferroportin protein in all tissues and showed that they die early in embryonic development, apparently because the embryos could not obtain iron from the mothers. We next used a genetic trick to preserve ferroportin expression in nutritive extraembryonic tissues while inactivating it in all cells of developing embryos. These animals survived through birth but developed severe iron deficiency and anemia in the first few days of life. We developed mice that lacked ferroportin in selected tissues, to clarify where its function is important. This work confirmed that ferroportin is the major (or only) molecule involved in exporting iron from intestinal absorptive cells and from macrophages. It also contributes to iron export from liver cells that harbor the body's iron stores. (This work is supported by a grant from the National Institutes of Health.)
The most common form of hereditary hemochromatosis results from a mutation in HFE, a molecule that normally helps to control the efficiency of intestinal iron absorption. We generated mice that produce no functional HFE protein and mice that produce a mutant HFE protein analogous to that seen in most human patients with HFE hemochromatosis. Both types of mice are faithful models of the human disease. In collaboration with Matthias Hentze, Martina Muckenthaler, and colleagues (European Molecular Biology Laboratory, Heidelberg), we found that mice lacking normal HFE have a defect in the production of the hormone hepcidin. Hepcidin controls how cells release iron, by binding to the ferroportin transporter protein and causing it to be destroyed. Inadequate hepcidin production could explain why patients with hemochromatosis develop iron overload. Consistent with this interpretation, our collaboration with Sophie Vaulont and colleagues (INSERM, Paris) showed that forced expression of hepcidin prevented hemochromatosis in HFE mutant mice. (This work is now supported by a grant from the National Institutes of Health.)
HFE normally forms a protein-protein complex with the transferrin (TF) receptor (TFR). TFR picks up circulating TF protein containing iron and brings it inside the cell, where DMT1 can help unload the iron. We suspected that the HFE-TFR complex is important for controlling the activity of HFE, but it was not clear how this would happen. To investigate this, we developed mice expressing a mutant TFR protein that could not interact with TF. By studying that mouse strain and comparing it to other mice lacking TFR or TF or HFE itself, we deduced that unbound HFE regulates hepcidin expression. It appears that TFR controls HFE activity by sequestering it when the body has too little iron. (This work is supported by a grant from the National Institutes of Health.)
Other genes are mutated in some patients with hemochromatosis. Patients with mutations in the gene encoding hepcidin develop very severe, early onset iron overload. Recently, it was reported that mutations in a novel gene, designated hemojuvelin (HJV), also cause severe hemochromatosis. There is evidence that HJV may be part of the same regulatory network as HFE and hepcidin. To study this in vivo, we disrupted the mouse Hjv gene. We found that mice lacking HJV develop severe hemochromatosis early in life. They produce almost no hepcidin hormone. Accordingly, there is much more ferroportin present in intestinal cells and macrophages. As a result, intestinal iron absorption is markedly increased and very little iron is stored in macrophages, leading to too much iron in the circulation.
Based on these results and others, we now propose that all known forms of hemochromatosis result from perturbations of the regulation of hepcidin hormone production. The consequence, too little hepcidin, leads to increased activity of the ferroportin iron transporter, explaining the increased intestinal iron absorption and increased tissue iron loading observed in patients.
Last updated July 20, 2005