title: Cell-specific regulation of Ferroportin transcription following experimentally-induced acute anemia in mice.
abstract: Ferroportin (FPN), the sole characterized iron exporter, is mainly controlled by the peptide hormone hepcidin in response to iron, erythroid factors, hypoxia, and inflammation. In addition, intracellular iron level controls FPN translation by modulating the binding of Iron Responsive Proteins at the 5'UTR of FPN mRNA. Recently, hypoxia inducible factor (HIF)2α has been shown to regulate FPN expression in intestinal cells. Here we show that, during experimentally-induced acute anemia in mice, FPN is regulated at transcriptional level in a cell-specific manner. FPN mRNA level increases in duodenum and spleen macrophages, whereas it does not change in liver and is strongly down-regulated in erythroid precursors. These results were confirmed in Caco2, Raw264.7 and K562 cells treated with a hypoxic stimulus. Moreover, we found a differential expression of HIF1α and HIF2α in cells and tissues that might account for the specificity of FPN regulation. Thus, hypoxia, by directly controlling hepcidin and its target FPN, orchestrates a complex regulatory network aimed at ensuring rapid iron recovery from the periphery and efficient iron utilization in the erythroid compartment.
authors.affiliation: Dept. of Genetics, Biology and Biochemistry, University of Torino, Italy.
authors.forename: Deborah
authors.initials: D
authors.lastname: Chiabrando
authors.forename: Veronica
authors.initials: V
authors.lastname: Fiorito
authors.forename: Samuele
authors.initials: S
authors.lastname: Marro
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Silengo
authors.forename: Fiorella
authors.initials: F
authors.lastname: Altruda
authors.forename: Emanuela
authors.initials: E
authors.lastname: Tolosano
mesh_terms: D000208:Acute Disease; D000740:Anemia / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000235:genetics* / Q000378:metabolism; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D027682:Cation Transport Proteins / Q000235:genetics* / Q000378:metabolism; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D004386:Duodenum / Q000378:metabolism; D005786:Gene Expression Regulation; D064451:Hepcidins; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D007501:Iron / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D009928:Organ Specificity; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013154:Spleen / Q000378:metabolism; D014158:Transcription, Genetic; D000098742:Ferroportin; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D023181:Antimicrobial Cationic Peptides; D051792:Basic Helix-Loop-Helix Proteins; D027682:Cation Transport Proteins; D064451:Hepcidins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007501:Iron; D012333:RNA, Messenger; D000098742:Ferroportin; D000099162:Endothelial PAS Domain-Containing Protein 1; C578702:HAMP protein, human; C579599:Hamp protein, mouse; C497443:Hif1a protein, mouse