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Hepatic HIF-2 down-regulates hepcidin expression in mice through epo-mediated increase in erythropoiesis. Haematologica. 2011 Dec 29; Authors: Mastrogiannaki M, Matak P, Mathieu JR, Delga S, Mayeux P, Vaulont S, Peyssonnaux C Abstract
Background. Iron metabolism, regulated by the iron hormone hepcidin, and oxygen homeostasis, dependent on HIF-hypoxia inducible factors, are strongly interconnected. We previously reported that in mice where both liver HIF-1 and HIF-2 are stabilized (the hepatocyte VHL knockout mouse model), hepcidin expression was strongly repressed and we hypothesized that HIF-2 could be the major regulatory component contributing to the hepcidin down-regulation. Design and Methods. We generated and analyzed hepatocyte-specific knockout mice harboring either HIF-2α deficiency (Hif2a KO) or constitutive HIF-2α stabilization (Vhlh/Hif1a KO) and ex vivo systems (primary hepatocyte cultures). Hif2a KO mice were fed an iron deficient diet for 2 months and Vhlh/Hif1a KO treated with neutralizing EPO antibody.Results. We demonstrate that HIF-2 is not involved 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 EPO production. Experiments in primary hepatocytes confirmed the non-autonomous role of HIF-2 in hepcidin regulation. Conclusions. While our results indicate that HIF-2 is not directly involved in hepcidin repression, they highlight the contribution of hepatic HIF-2 to repress hepcidin through EPO-mediated increased erythropoiesis, a result of potential clinical interest.
PMID: 22207682 [PubMed - as supplied by publisher] Read more |
