Iron Metabolism Depends on Hepcidin

An excess of iron is also toxic, as it facilitates the generation of free radicals that can attack the liver, heart and pancreas. This is the case in hereditary hemochromatosis, a genetic disorder that in 80% of cases is linked to a point mutation in the Hfe-1 gene, leading to excessive iron uptake by the intestinal tract.

Researchers from the Institut Cochin (Paris, France) report in the April 2, 2002, issue of the Proceedings of the National Academy of Sciences that they have produced a transgenic mouse with abnormal iron metabolism, namely, premature aging of the pancreas and liver, which take on an abnormal brown color--a sign of iron accumulation. These hemochromatoic mice lack a transcription factor known as USF2 (upstream stimulatory factor 2), thought to be involved in glucose metabolism.

One abnormally expressed gene in these mice was found to code for hepcidin. The researchers believe that hepcidin acts essentially as a true hormone, inhibiting iron uptake by intestinal cells. They also believe that when hepcidin dysfunctions, the body has no way of limiting iron absorption into the bloodstream.

To test this hypothesis, iron levels were determined in a transgenic mouse model lacking USF2 but with an intact hepcidin gene. These mice had normal levels of iron. A second mouse model was then developed whose livers overproduced hepcidin. Almost all the newborn animals from this group were smaller than normal, had very pale skin and no hair, were profoundly anemic, and died within hours of birth--unless they received an injection of iron. Some animals producing less hepcidin were less severely anemic and survived without treatment.

These results, say the researchers, open up the short-term possibility of a diagnostic test based on measurement of serum hepcidin. In the longer term, the development of hepcidin agonists and antagonists may well transform the treatment of disorders caused by abnormal iron homeostatsis.




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