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

Abstract

The online version of this article has a Supplementary Appendix. BackgroundIron 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. Design and MethodsWe generated and analyzed hepatocyte-specific knockout mice harboring either hypoxiainducible 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. ResultsWe 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. ConclusionsWhile 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.

Four-Week Studies of Oral Hypoxia-Inducible Factor–Prolyl Hydroxylase Inhibitor GSK1278863 for Treatment of Anemia

“…[39][40][41] In addition to direct suppression of hepcidin by erythropoiesis, HIF mechanisms independent of erythropoiesis have also been implicated in decreasing hepcidin, 42 although this view is somewhat controversial. 43 Pharmacologic inhibition of HIF-prolyl hydroxylase has been shown to stimulate EPO production in both animal models 26 and in humans [27][28][29][30] and to reduce circulating levels of hepcidin. [28][29][30][31][32] In these studies, hepcidin was only reduced from baseline within the 5-mg GSK1278863 arm in the nondialysis study, the only dose arm that raised mean hemoglobin from baseline.…”

Understanding complexity in the HIF signaling pathway using systems biology and mathematical modeling

“…At a systemic level, hypoxia-activated HIF induces erythropoietin expression in interstitial kidney and liver cells that subsequently increases erythropoiesis in the bone marrow [15,16]. In addition, HIF-driven increase of the serum erythropoietin levels represses the hamp gene that encodes the hepatocyte-specific iron homeostasis regulator hepcidin [17][18][19]. The subsequent drop of serum hepcidin results in elevated iron release from the intestinal epithelium supplying the increased iron demand of the expanded erythropoiesis [20].…”

Differential diagnosis of anemia in pregnant women

“…При гипоксии, с которой также связана активация ýритропоýза, продуцируется гипок-сия-индуцируемый фактор (HIF), предположи-тельно связывающийся с промоторным участком HAMP [48] и угнетающий продукцию гепсидина. Помимо ýтого представлены доказательства мо-дуляции звеньев BMP-SMAD-пути при гипоксии [49][50][51].…”

“…При гипоксии, с которой также связана активация ýритропоýза, продуцируется гипок-сия-индуцируемый фактор (HIF), предположи-тельно связывающийся с промоторным участком HAMP [48] и угнетающий продукцию гепсидина. Помимо ýтого представлены доказательства мо-дуляции звеньев BMP-SMAD-пути при гипоксии [49][50][51].В условиях развития в организме патологиче-ских состояний, ассоциированных с воспалением, регуляция ýкспрессии гепсидина осуществляется через повышенную продукцию цитокинов с вов-лечением JAK-STAT-пути. Доказано, что промо-торный участок гена HAMP содержит сайт для связывания STAT3 [52], а самым сильным актива-тором продукции гепсидина является интерлей-кин (IL) 6 [53,54].…”