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Iron exporter revealed that may explain common human disorder

The first direct evidence that a single protein is critical in the cellular export of iron may help to explain human hemochromatosis, researchers report in the March issue of Cell Metabolism.

Hemochromatosis--which affects one in every 200 to 300 people in Western populations --causes tissues of the body to become overloaded with iron. Left untreated, the hereditary disease can lead to organ failure.

The new work, led by researchers at the Children's Hospital Boston and Harvard Medical School, finds that the protein ferroportin is the major, if not the only, iron exporter that functions in key sites of iron absorption and release in the body. The findings suggest that the iron accumulation seen in those with hemochromatosis may stem from a loss of control over iron export through ferroportin, the researchers said.

"Iron is essential in the body and abundant in the environment, but it's also very reactive and damaging when in excess," said Nancy Andrews, senior author of the study. "Mammals have therefore evolved mechanisms to get enough iron from the diet, but not too much."

Iron is an essential ingredient of hemoglobin, the protein molecule in red blood cells that carries oxygen from the lungs to the body's tissues. Unlike other metals, iron cannot be eliminated through the liver or kidneys, Andrews explained. Iron balance is maintained instead through the complex regulation of tissues that transport, store, and utilize iron.

Mammals, including humans, initially obtain iron from their mothers. After birth, the intestine absorbs dietary iron and releases it into the bloodstream where developing red blood cells incorporate the iron into hemoglobin. When red blood cells die, macrophage cells consume them and recycle the iron they contain. Macrophages and liver cells also store any excess iron.

Earlier work had identified a single protein that imports iron into cells. However, the evidence for ferroportin's role in exporti ng iron back out of cells remained indirect. To determine which cells depend on ferroportin, the researchers inactivated the protein in mice, both globally and in select tissues.

Animals completely lacking ferroportin died early in development due to a failure of iron transfer from mother to embryo. Mice deficient for ferroportin in all tissues except those critical for maternal nutrient transfer survived but quickly became anemic after birth due to iron deficiency in the blood. Examination of the animals' intestine, liver, and spleen revealed an accumulation of iron within cells, indicating an inability of cells to release iron once absorbed.

Mice lacking ferroportin only in intestinal cells also developed severe iron deficiency anemia, further confirming the protein's role in iron absorption.

The findings offer insight into the underlying basis for hemochromatosis, Andrews said. The researchers propose that, in patients with the disease, perturbations in iron homeostasis result from a failure to control iron export through ferroportin, leading to increased iron release from macrophages and enhanced intestinal absorption. Indeed, patients with the disease exhibit a deficiency of hepcidin, a hormone that binds ferroportin and targets it for destruction.

Drugs that inhibit or degrade ferroportin might therefore curb the iron overload suffered by those with hemochromatosis, Andrews said. Those with excess iron for other reasons, such as repeated blood transfusions, might also benefit from such a drug, she added.

The other members of the research team include Adriana Donovan from Children's Hospital Boston and Harvard Medical School; Christine A. Lima from Children's Hospital Boston and Howard Hughes Medical Institute; Jack L. Pinkus and Geraldine S. Pinkus from Brigham and Women's Hospital; Leonard I. Zon and Nancy C. Andrews from Children's Hospital Boston, Harvard Medical School, and Howard Hughes Medical Institute; and Sylvie Robine from Equipe de Morphogen├Ęse et Signalisation Cellulaires, Institut Curie. This work was supported by P01 HL32262 (N.C.A.) and K01 5 K01 DK64924-02 (A.D.). The authors have no competing financial interests.

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Adriana Donovan, Christine A. Lima, Jack L. Pinkus, Geraldine S. Pinkus, Leonard I. Zon, Sylvie Robine, and Nancy C. Andrews: "The iron exporter ferroportin/Slc40a1 is essential for iron homeostasis"

Publishing in Cell Metabolism, Volume 1, Number 3, March 2005, pages 191-200. www.cellmetabolism.org


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Source:Cell Press


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