"Heme" - an iron-transporting molecule most well known as part of hemoglobin - "is needed by all cells because it's required for so many cell functions," Janis Abkowitz told BioWorld Today. "But it's toxic, so cells need very elaborate mechanisms . . . to use it and control it."

In the Feb 8, 2008, issue of Science, Abkowitz, professor of medicine at the University of Washington Medical School, and her colleagues there and at the University of Rochester and the University of Utah, described new findings about one such control: the feline leukemia virus receptor. That receptor appears to transport heme out of cells when its levels are too high, and can shunt heme from the liver to the bile in what Abkowitz termed "a previously unrecognized way for iron to exit the body."

Abkowitz noted that "receptor" is itself a misnomer for the protein, which is "a ubiquitous transporter molecule that the virus has usurped," she said. The researchers focused on the feline leukemia virus receptor because infection with the virus, though it happens in all cells of the bone marrow, uniquely affects the production of red blood cells over white blood cells and platelets.

The researchers engineered mice lacking one copy of the feline leukemia virus receptor gene, as well as inducible knockouts. When animals each lacking one copy were bred, none of the more than 100 resulting progeny lacked both copies of the gene. Such embryos died during development. The embryos had anatomical features that resembled those seen in Diamond-Blackfan anemia; inducible knockouts also developed severe anemia that resembled Diamond-Blackfan anemia.

Research into that particular anemia, which was first described in the 1930s, was discussed in the plenary session of last year's American Society for Hematology annual meeting, where researchers showed data suggesting that many cases of Diamond-Blackfan anemia are due to mutations in ribosomal proteins.

Abkowitz stressed that the causes of Diamond-Blackfan anemia are still controversial, but also said that the work presented at ASH fits with the current research in Science. Both findings suggested that severe blood cell anemia develops when heme is out of balance with globin.

"Heme synthesis initiates when iron is available," she said. And once heme is being made, it turns on the production of globin to make hemoglobin. But because heme itself turns on globin, "there is a brief period during development when heme is going strong and globin is not yet available."

In Diamond-Blackfan anemia, globin becomes available more slowly due to mutations in ribosomal genes that slow down protein synthesis; when the FLV receptor is missing, heme cannot be exported. The next effect of both scenarios is that the red blood cells are killed off by excess heme.

The researchers also investigated the consequences of receptor deletion on the liver and bile. They found that mice lacking the receptor developed iron overload in the liver and subsequent problems with their bile system. They wrote in their paper that "one possibility consistent with our data is that FLV [receptor] exports heme from liver into bile in a previously unrecognized way for iron to exit the body."

Current theory holds that iron levels are regulated via uptake of dietary iron and its recycling via macrophages, but that short of bleeding, there is no way for iron to leave the body.

Abkowitz said if such a pathway truly exists, it could be targeted therapeutically, possibly leading to "novel therapies for pure red cell aplasia, Diamond-Blackfan anemia and myelodysplasia, for the anemia of chronic inflammation and for hemochromatosis."

That latter disease, characterized by iron overload, also was the subject of another paper last week. In the February 2008 issue of Cell Metabolism, German researchers presented new work showing that hemochromatosis results from a gene defect in liver tissue.

Because iron is recycled very efficiently, iron uptake in the intestine needs to be limited to avoid getting too much of a good thing. Previous research has shown that such limitation is disrupted when a gene known as the HFE gene is mutated, resulting in hemochromatosis or iron overload. But where exactly the gene was causing the hemochromatosis has been unclear up to now.

The prime suspect organ has been the intestine, where iron is absorbed; but a recent paper where mice were lacking HFE specifically in intestinal cells had not led to animals with hemochromatosis symptoms.

In contrast, when scientists engineered mice that lacked HFE specifically in the liver, the animals had all the classical features of hemochromatosis including elevated iron levels in both blood plasma and the liver. The authors believe that Hfe protein signals the amount of iron in the body to liver cells. When iron levels are high, the liver makes a hormone known as hepcidin that signals to the intestine to reduce iron uptake. When HFE is mutated, less hepcidin is made and more iron is taken up.

The authors concluded that "knowing that Hfe acts in hepatocytes to regulate hepcidin expression represents a critical step toward understanding [hereditary hemochromatosis.]"

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