Hepatic hypoxia-inducible factor-2 down-regulates hepcidin expression in mice through an erythropoietin-mediated increase in erythropoiesis

ArticleinHaematologica 97(6):827-34 · December 2011with23 Reads
DOI: 10.3324/haematol.2011.056119 · Source: PubMed
Abstract
Iron metabolism, regulated by the iron hormone hepcidin, and oxygen homeostasis, dependent on hypoxia-inducible factors, are strongly interconnected. We previously reported that in mice in which both liver hypoxia-inducible factors-1 and -2 are stabilized (the hepatocyte von Hippel-Lindau knockout mouse model), hepcidin expression was strongly repressed and we hypothesized that hypoxia-inducible factor-2 could be the major regulatory component contributing to the hepcidin down-regulation. We generated and analyzed hepatocyte-specific knockout mice harboring either hypoxia-inducible factor-2α deficiency (Hif2a knockout) or constitutive hypoxia-inducible factor-2α stabilization (Vhlh/Hif1a knockout) and ex vivo systems (primary hepatocyte cultures). Hif2a knockout mice were fed an iron-deficient diet for 2 months and Vhlh/Hif1a knockout mice were treated with neutralizing erythropoietin antibody. We demonstrated that hypoxia-inducible factor-2 is dispensable in hepcidin gene regulation in the context of an adaptive response to iron-deficiency anemia. However, its overexpression in the double Vhlh/Hif1a hepatocyte-specific knockout mice indirectly down-regulates hepcidin expression through increased erythropoiesis and erythropoietin production. Experiments in primary hepatocytes confirmed the non-autonomous role of hypoxia-inducible factor-2 in hepcidin regulation. While our results indicate that hypoxia-inducible factor-2 is not directly involved in hepcidin repression, they highlight the contribution of hepatic hypoxia-inducible factor-2 to the repression of hepcidin through erythropoietin-mediated increased erythropoiesis, a result of potential clinical interest.
    • "erythropoietin levels represses the HAMP gene that encodes the hepatocyte-specific iron homeostasis regulator hepcidin [19][20][21]. The subsequent drop of serum hepcidin results in elevated iron release from the intestinal epithelium supplying the increased iron demand of the expanded erythropoiesis [22] . "
    [Show abstract] [Hide abstract] ABSTRACT: Hypoxia is a common micro-environmental stress which is experienced by cells during a range of physiologic and pathophysiologic processes. The identification of the hypoxia-inducible factor (HIF) as the master regulator of the transcriptional response to hypoxia transformed our understanding of the mechanism underpinning the hypoxic response at the molecular level and identified HIF as a potentially important new therapeutic target. It has recently become clear that multiple levels of regulatory control exert influence on the HIF pathway giving the response a complex and dynamic activity profile. These include positive and negative feedback loops within the HIF pathway as well as multiple levels of crosstalk with other signaling pathways. The emerging model reflects a multi-level regulatory network that affects multiple aspects of the physiologic response to hypoxia including proliferation, apoptosis, and differentiation. Understanding the interplay between the molecular mechanisms involved in the dynamic regulation of the HIF pathway at a systems level is critically important in defining new appropriate therapeutic targets for human diseases including ischemia, cancer, and chronic inflammation. Here, we review our current knowledge of the regulatory circuits which exert influence over the HIF response and give examples of in silico model-based predictions of the dynamic behaviour of this system.
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    • "In particular, it has been shown that IRP-1 also acts as negative translational regulator of hypoxia-inducible factor 22 (HIF22) [367]. This interference affects several downstream targets of HIF22 such as erythropoietin (EPO) expression and by this erythropoiesis and hepcidin expression368369370371372 as well as transcriptional activation of Fpn and DMT-1373374375 in addition to the IRP-1/mRNA-based regulation. Since HIF22, like HIF11, also affects tumor progression and tumor stem cell function [376,377], IRP-1 could also play a role in tumorigenesis. "
    [Show abstract] [Hide abstract] ABSTRACT: Iron and oxygen share a delicate partnership since both are indispensable for survival, but if the partnership becomes inadequate, this may rapidly terminate life. Virtually all cell components are directly or indirectly affected by cellular iron metabolism, which represents a complex, redox-based machinery that is controlled by, and essential to, metabolic requirements. Under conditions of increased oxidative stress—i.e., enhanced formation of reactive oxygen species (ROS)—however, this machinery may turn into a potential threat, the continued requirement for iron promoting adverse reactions such as the iron/H2O2-based formation of hydroxyl radicals, which exacerbate the initial pro-oxidant condition. This review will discuss the multifaceted homeodynamics of cellular iron management under normal conditions as well as in the context of oxidative stress.
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    • "Human ferroportin mutations have been reported [11,12] that appear to prevent hepcidin binding and create iron overload states. Hepcidin may itself be regulated by a bone marrow suppressor of hepcidin that responds to increased erythropoietin from hypoxia or hemorrhage [13,14]. Other homeostatic mechanisms not appearing to be reliant on hepcidin include hypoxia and cellular iron deficiency. "
    [Show abstract] [Hide abstract] ABSTRACT: An elderly physician with iron deficiency anemia and early stage colon cancer localized in the cecum was treated successfully with laparoscopic right hemicolectomy. Despite treatment, her iron deficiency anemia persisted. Subsequent investigations revealed occult celiac disease that completely resolved with a gluten-free diet alone. Iron deficiency anemia in celiac disease may have multiple causes including reduced duodenal iron absorption because of reduced absorptive surface area, alterations or mutations in iron regulatory proteins critical for normal iron absorption, superimposed occult blood loss from different causes including benign and malignant small bowel ulceration, and low grade intravascular hemolysis. Although iron deficiency anemia may be the sole presenting clinical manifestation of occult celiac disease without other typical symptoms, such as diarrhea or weight loss, a very thorough gastrointestinal assessment is essential to exclude other causes of iron deficiency anemia. Conversely, persistent or refractory iron deficiency anemia may represent a clue to unrecognized celiac disease, even in the elderly
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