Hepcidin/Ferroportin/HIF-2a Regulation of Iron Metabolism at the Systemic and Cellular Level
Schwartz, Andrew
2019
Abstract
Iron is a metal micronutrient that is required by all living organisms, from single cell bacteria to complex, multicellular organisms that include humans. Systemic iron handling in mammals requires, i) the liver-derived, endocrine hormone, hepcidin, and ii) the iron/oxygen sensitive intestinal transcription factor, hypoxia-inducible factor (HIF)- 2α. The function of hepcidin is to bind to the only mammalian iron exporter, ferroportin, resulting in ferroportin internalization from the plasma membrane, intracellular degradation, and a reduction of iron export into circulation. At the intestinal level, HIF-2α controls iron absorption by regulating the transcription of apical and basolateral iron transporters. This dissertation focuses on the integration of hepcidin/ferroportin/HIF-2α signaling in iron homeostasis at the systemic and cellular level, in physiological and pathological contexts. The data in this work unveil a hetero-tissue crosstalk mechanism, whereby hepatic hepcidin regulated intestinal HIF-2α during states of systemic iron deficiency, anemia, and iron overload. I show that the hepcidin target, ferroportin, controlled cell-autonomous iron efflux to stabilize and activate HIF-2α by regulating the activity of iron-dependent intestinal prolyl hydroxylase domain enzymes. Pharmacological blockade of HIF-2α using a clinically relevant and highly specific inhibitor successfully treated iron overload in a mouse model of hepcidin-deficiency. In addition to iron overload, over one billion people worldwide suffer from iron- deficiency anemia (IDA), a state of systemic iron insufficiency that limits the production red blood cells and leads to tissue hypoxia and intracellular iron stress. Using a novel genetic mouse model of tamoxifen-inducible intestinal ferroportin deletion, I revealed a robust phenotype of progressive IDA that developed in as little as three months. At end- stage IDA, tissue-specific transcriptional stress responses were observed, whereby the heart showed little to no hypoxic and iron stress as compared to other peripheral organs. However, morphometric and echocardiographic analysis revealed massive cardiac hypertrophy and chamber dilation, albeit with increased cardiac output at very low basal heart rates. These data revealed a model of end-stage IDA that can be used in future studies to investigate IDA progression and cell-specific responses to hypoxic and iron stress. We lastly investigated mechanisms of local iron handling and extra-hepatic hepcidin expression in the context of colorectal cancer (CRC), a disease in which cellular iron metabolism is perturbed to enhance growth and survival. I revealed that epithelial cells in CRC produce an ectopic source of hepcidin that is necessary and sufficient to control CRC tumorigenesis. Hepcidin promoter analysis demonstrated that hypoxia and its downstream transcription factor, HIF-2α, are sufficient to activate the hepcidin promoter in CRC-derived cell lines. These data suggest that HIF-2α induces hepcidin in the tumor epithelium to establish a paracrine/autocrine axis to degrade local ferroportin and sequester iron in colorectal tumors in order to maintain iron-dependent cancer cell metabolism. Overall, the data presented in this dissertation unveil mechanisms by which systemic iron handling interacts and integrates with local iron handling, providing insight into targeted therapies for iron-related disorders and adjuvant strategies for cancers.Subjects
This dissertation provides the biological framework for targeted therapies for iron-related disorders and adjuvant strategies for cancers.
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