The Role of Hypoxia-Inducible Factors in the Regulation of Systemic Iron Homeostasis.

Abstract

Disorders of Iron Homeostasis affect over a billion people worldwide. These disorders can be grouped according to iron deficiency, the major cause of anemia, and iron overload, the major cause of death in patients with hemochromatosis. Anemia is managed with blood transfusions or iron supplementation, and hemochromatosis is treated with chelation and phlebotomy. These treatments are effective in many cases, but are often poorly tolerated and can take years to improve the quality of life for patients. The present work describes a novel signaling pathway by which intestinal iron absorption can be controlled by oxygen signaling. This thesis demonstrates that during hemolytic anemia, iron absorption is increased in a HIF-2α-dependent manner, and loss of intestinal HIF-2α inhibits hematopoietic recovery. In addition, β-thalassemia is a genetic disorder characterized by anemia and complicated by iron overload, which is the major cause of death in patients. This is thought to be due to frequent blood transfusions required to correct anemia, but many patients develop iron overload in the absence of transfusions. Using a mouse model of the disease, this thesis shows that loss of intestinal HIF-2α prevents iron overload. Together, these data demonstrate that intestinal HIF-2α activity is essential for adaptive changes in iron absorption and could be targeted therapeutically to treat anemia and iron overload. Besides the intestine, the liver is also a critical sensor and regulator of iron homeostasis. Hepcidin is an antimicrobial peptide produced in the liver which acts to restrict iron availability by blocking intestinal iron absorption and release of iron from macrophages, which recycle iron from senescent erythrocytes. Hepcidin is regulated by multiple signaling pathways, and one of the least understood regulators of hepcidin expression is hypoxia. The present work demonstrates that hypoxic repression of hepcidin requires the hypoxia-inducible transcription factors (HIFs) and is mediated by a decrease in C/EBPα protein in the liver. Subsequently, this work shows that ethanol-mediated hepcidin repression, which exacerbates liver injury, requires HIF activity. Together, these models demonstrate that HIFs are the central regulators of iron homeostasis and can be targeted therapeutically to manage diseases of both anemia and iron overload.