title: The liver-specific microRNA miR-122 controls  systemic iron homeostasis in mice.
abstract: Systemic iron homeostasis is mainly controlled by the liver through synthesis of the peptide hormone hepcidin (encoded by Hamp), the key regulator of duodenal iron absorption and macrophage iron release. Here we show that the liver-specific microRNA miR-122 is important for regulating Hamp mRNA expression and tissue iron levels. Efficient and specific depletion of miR-122 by injection of a locked-nucleic-acid-modified (LNA-modified) anti-miR into WT mice caused systemic iron deficiency, characterized by reduced plasma and liver iron levels, mildly impaired hematopoiesis, and increased extramedullary erythropoiesis in the spleen. Moreover, miR-122 inhibition increased the amount of mRNA transcribed by genes that control systemic iron levels, such as hemochromatosis (Hfe), hemojuvelin (Hjv), bone morphogenetic protein receptor type 1A (Bmpr1a), and Hamp. Importantly, miR-122 directly targeted the 3′ untranslated region of 2 mRNAs that encode activators of hepcidin expression, Hfe and Hjv. These data help to explain the increased Hamp mRNA levels and subsequent iron deficiency in mice with reduced miR-122 levels and establish a direct mechanistic link between miR-122 and the regulation of systemic iron metabolism.
authors.affiliation: Department of Pediatric Hematology, Oncology, and Immunology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Mirco
authors.initials: M
authors.lastname: Castoldi
authors.forename: Maja
authors.initials: M
authors.lastname: Vujic Spasic
authors.forename: Sandro
authors.initials: S
authors.lastname: Altamura
authors.forename: Joacim
authors.initials: J
authors.lastname: Elmén
authors.forename: Morten
authors.initials: M
authors.lastname: Lindow
authors.forename: Judit
authors.initials: J
authors.lastname: Kiss
authors.forename: Jens
authors.initials: J
authors.lastname: Stolte
authors.forename: Richard
authors.initials: R
authors.lastname: Sparla
authors.forename: Lorenza A
authors.initials: LA
authors.lastname: D'Alessandro
authors.forename: Ursula
authors.initials: U
authors.lastname: Klingmüller
authors.forename: Robert E
authors.initials: RE
authors.lastname: Fleming
authors.forename: Thomas
authors.initials: T
authors.lastname: Longerich
authors.forename: Hermann J
authors.initials: HJ
authors.lastname: Gröne
authors.forename: Vladimir
authors.initials: V
authors.lastname: Benes
authors.forename: Sakari
authors.initials: S
authors.lastname: Kauppinen
authors.forename: Matthias W
authors.initials: MW
authors.lastname: Hentze
authors.forename: Martina U
authors.initials: MU
authors.lastname: Muckenthaler
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites / Q000235:genetics; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000235:genetics; D015536:Down-Regulation; D005260:Female; D020869:Gene Expression Profiling; D006411:Hematopoiesis, Extramedullary / Q000235:genetics / Q000502:physiology; D000071020:Hemochromatosis Protein; D064451:Hepcidins; D015395:Histocompatibility Antigens Class I / Q000235:genetics; D006706:Homeostasis; D007501:Iron / Q000097:blood / Q000378:metabolism*; D000090463:Iron Deficiencies; D008099:Liver / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D009841:Oligonucleotides / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; D023181:Antimicrobial Cationic Peptides; C579599:Hamp protein, mouse; D000071020:Hemochromatosis Protein; D064451:Hepcidins; C499535:Hfe protein, mouse; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; D035683:MicroRNAs; C544354:Mirn122 microRNA, mouse; D009841:Oligonucleotides; D012333:RNA, Messenger; C477371:locked nucleic acid; D007501:Iron; C498212:Bmpr1a protein, mouse; D052005:Bone Morphogenetic Protein Receptors, Type I