New Discoveries in Oxygen Homeostasis
and Iron Homeostasis

By Zoe L. Larned, M.D., and
Thomas L. Ortel, M.D., Ph.D.

Oxygen homeostasis is a process that is carefully regulated in healthy individuals. Scientists are gaining insights into this process of regulation through better understanding of oxygen dependent gene expression and the changes that occur when there are abnormalities in these genes. Drs. H. Franklin Bunn and Josef T. Prchal provided a scientific review of some of these findings during Sunday's scientific committee session entitled Hemoglobin and Oxygen Homeostasis.

Hypoxia-inducible factor-1 (HIF-1) is transcription factor composed of two subunits, HIF-1± and HIF- 1², and controls a vast array of genes, including genes involved in the following: erythopoeisis, vasculogenesis, embryogenesis and tumor development. While both subunits are constitutively expressed, the HIF- 1± subunit is inactive under normal oxygen conditions since it is constantly degraded via an oxygendependent degradation domain (ODD) that is controlled by the ubiquitin-proteasome pathway. This process is also mediated by other important factors including the von Hippel-Lindau (VHL) protein.

In hypoxic conditions HIF-1± becomes upregulated. In this setting HIF can then bind to promoter regions for other genes induced by hypoxia, including: erythropoietin, vascular endothelial growth factor (VEGF), and genes with important roles in the metabolism of iron and cell survival. This upregulation, confirmed by findings of elevated HIF-1± levels, has been seen to occur in a variety of disease processes including malignant tumors and tissue ischemia. It therefore provides an interesting target for therapy. Using these findings, it can be hypothesized that treatments altering HIF-1± expression could be utilized to change specific tissue environments. For example, many tumors create protective hypoxic environments in which they are able to grow, invade, and metastasize. Therapy that downregulates the HIF-1± that becomes expressed in these hypoxic environments could potentially alter the tumors' ability to thrive.

Studies of inherited disorders of hypoxia have also furthered the understanding of how oxygen homeostasis is regulated. Patients with Chuvash polycythemia, an inherited (autosomal recessive) disorder endemic to the mid-Volga River region, have been found to have a missense mutation of VHL (598C>T). This impairs the interaction between VHL and HIF-1± resulting in increased expression of HIF and genes downstream, such as erythropoietin and VEGF. While these individuals have high erythropoietin resulting in polycythemia and its disease sequelae, the effect of upregulation of VEGF has not yet been determined although these individuals typically do not have increased rates of tumors. Additional mutations in polycythemic individuals have also been identified and others are being investigated. Studies regarding the pathogenesis of anemia of chronic disease have led to an increased understanding of the role of iron homeostasis. Normally, iron homeostasis is a carefully regulated balance of dietary iron absorption and total body iron requirements. Patients with anemia resulting from a range of chronic disease processes (infection, arthropathies, and malignancy…) have been shown to have an upset of this balance at both the storage end, with evidence of macrophage iron retention leading to decreased circulating iron, and at the intestinal iron absorption end where there are also marked impairments.

The question as to how communication occurs between the intestinal cells at the intestinal absorption level and the iron held in storage to maintain this careful balance has been an area of recent important discoveries, particularly with the discovery of hepcidin. Hepcidin is a circulating peptide produced by the liver that has been shown to have an important role in regulating the balance of iron. It provides an exciting area for which future therapies may be developed or targeted for a multitude of disorders of iron metabolism.

On Saturday, Dr. Nancy C. Andrews provided a scientific review of the role of hepcidin, the pathophysiology of anemia of chronic disease, and alterations in iron homeostasis in the scientific committee session entitled Iron and Heme Cellular Iron Uptake and Export.