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Researchers have gained new insights into the most common
inherited disease in the Western world--hemochromatosis. The
condition affects about one in every 250 people and can be
fatal if left untreated.
Normally, when the body has enough iron, the cells stop absorbing
it from food and if there is too little iron, they absorb
more. If this system breaks down, a person can absorb too
much iron from the diet, leading to hemochromatosis (iron
overload).
While the mutation that causes the condition was thought
to affect primarily the intestine, researchers in the research
group of Matthias Hentze at the European Molecular Biology
Laboratory in Heidelberg (EMBL) and researchers from Harvard
Medical School (U.S.) have linked the response of a gene in
the liver to the disease.
The finding may lead to a new understanding of how hemochromatosis
develops.
Sufferers of hemochromatosis have inherited a defective copy
of a gene called Hfe from each parent. The defect leads a
person's intestine to absorb too much iron from his or her
diet. Over the course of many years, this builds up, and by
middle age, the overload may be very serious.
Until now, most researchers have thought that the problem
stems from a faulty intestinal signal that there is too little
iron, leading cells in the intestines to produce more transport
proteins that draw iron inside.
However, the current study shows that the link between Hfe
and iron is probably in the liver, rather than the intestine.
EMBL researchers investigated iron absorption with a technology
called DNA chips, which allows scientists to monitor how a
cell's genes respond to changes such as a raise in levels
of iron. They put together a set of probes to watch for changes
in 300 genes known to have some connection to iron.
Meanwhile, Harvard scientists were investigating hemochromatosis
in mice and developed strains of mice without Hfe, or with
the mutant version found in hemochromatosis. They found that
both strains absorbed too much iron and exhibited the symptoms
of the disease.
The DNA chips were used to compare cells taken from these
mice and their healthy cousins. In the former model, cells
with defective Hfe were expected to behave like healthy mice
with an iron deficiency, producing more iron-absorbing proteins
in the intestine. However, that wasn't the case so researchers
started to look for other effects of mutant Hfe.
They found that hepcidin, a molecule in the liver, wasn't
being activated properly.
When iron levels rise in a healthy mouse, its liver produces
more hepcidin, and hepcidin acts like a hormone to reduce
iron absorption by the intestine. This didn't happen in mice
with mutant or missing Hfe even when the researchers directly
injected them with iron, giving proof that Hfe is necessary
to make a connection between iron and hepcidin.
How can hepcidin expression by the liver change iron absorption
among intestinal cells? Although a lot of questions remain,
according to researchers, without hepcidin the body can't
seem to halt an intestinal molecule called Cybrd1.
Normally iron atoms carry three positive charges; in that
form they can't be brought into cells. Cybrd1 works by reducing
the number of charges to two, making iron transportable. If
it were active all the time, a lot more of the body's iron
would be absorbable. When it isn't active, there is very little
to be absorbed. Hepcidin's normal function might be to lock
down Cybrd1, thereby shutting down the supply of available
iron. This would make activating hepcidin, which can't happen
with a mutant form of Hfe, essential to stopping the flow
of iron into the body.
Due to these findings, the focus of hemochromatosis research
will likely turn to the liver in order to investigate the
circuit that connects iron, Hfe and hepcidin. Additionally,
the findings suggest a link between the body's uptake of iron
and the immune system, where hepcidin also plays a role.
Eurekalert.org
April 25, 2003
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