Scientists at the University of California, San Diego (UCSD) have determined a key mechanism by which the body regulates iron metabolism, a discovery that may provide new approaches for the treatment of anemia.
The findings, which are reported this week in the online publication of The Journal of Clinical Investigation , represent a collaborative effort between the laboratories of Randall Johnson, Ph.D., UCSD professor of biology and Victor Nizet, M.D., professor of pediatrics and pharmacy at the UCSD School of Medicine and Skaggs School of Pharmacy and Pharmaceutical Sciences.
Iron is essential for many normal biological processes including the production red blood cells that deliver oxygen to the body's tissues. By studying the regulation of iron and production of red blood cells in mice, the researchers established the relationship between a pair of proteins that play a central role in monitoring a hormone called hepcidin.
The hepcidin hormone is a peptide, or small protein, that is synthesized in the liver and regulates the levels of iron in the body. It prevents the body from absorbing more iron than is needed from food or supplements, and blocks the export of iron from cells.
Patients with cancer, chronic inflammatory diseases or infections often develop high levels of hepcidin, which reduces the amount of iron available to support the production of new red blood cells. Consequently, such patients suffer from low red blood cell production, or anemia.
To properly respond to anemia, the body must somehow reduce hepcidin in order to increase the iron that is needed for red blood cell production. Until now, scientists didn't clearly understand the mechanisms by which hepcidin itself is regulated.
The UCSD research team discovered that a protein known as hypoxia-inducible transcription factor (HIF) is critical in orchestrating the proper hepcidin response in the liver. In turn, HIF levels are controlled on a minute-by-minute basis by the action of another protein known as von-Hippel Lindau factor (vHL.)
“The vHL factor works to lower HIF levels whenever oxygen is high or iron is abundant,” said Johnson. “When iron levels and oxygen delivery to the tissues drop, as is the case in anemia, vHL ceases its action and HIF is preserved.”
Previous research had shown that HIF is responsible for stimulating erythropoietin (EPO), a hormone that instructs the bone marrow to produce new red blood cells. The UCSD team made the critical and novel observation that HIF also strongly inhibits the production of hepcidin in the liver.