title: Hypoxia-inducible factor-2α mediates the adaptive increase of intestinal ferroportin during iron deficiency in mice.
abstract: OBJECTIVE
  Iron deficiency and iron overload affect over a billion people worldwide. Dietary iron absorption in the small intestine is required for systemic iron homeostasis. Ferroportin (FPN) is the only characterized, mammalian, basolateral iron exporter. Despite the importance of FPN in maintaining iron homeostasis, its in vivo mechanisms of regulation are unclear.
  
  
  METHODS
  Systemic iron homeostasis was assessed in mice with intestine-specific disruption of genes encoding the von Hippel-Lindau tumor suppressor protein (Vhl), hypoxia-inducible factor (HIF)-1α, HIF-2α, and aryl hydrocarbon nuclear translocator (ARNT).
  
  
  RESULTS
  We observed biphasic regulation of Fpn during iron deficiency. Fpn was rapidly induced under conditions of low iron, which required the transcription factor HIF-2α. Targeted disruption of HIF-2α in the intestine inhibited Fpn induction in mice with low iron, through loss of transcriptional activation. Analysis of the Fpn promoter and in vivo chromatin immunoprecipitation assays demonstrated that HIF-2α directly binds to the Fpn promoter and induces its expression, indicating a mechanism of transcriptional regulation of Fpn following changes in systemic levels of iron. During chronic iron deficiency, FPN protein levels also increased, via increased stability through a HIF-2α-independent pathway.
  
  
  CONCLUSIONS
  In mice, expression of the gene that encodes Fpn and its protein levels are regulated by distinct pathways to provide a rapid and sustained response to acute and chronic iron deficiency. Therapies that target FPN might be developed for patients with iron-related disorders.
authors.affiliation: Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor Michigan, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Taylor
authors.forename: Aijuan
authors.initials: A
authors.lastname: Qu
authors.forename: Erik R
authors.initials: ER
authors.lastname: Anderson
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Matsubara
authors.forename: Angelical
authors.initials: A
authors.lastname: Martin
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
authors.forename: Yatrik M
authors.initials: YM
authors.lastname: Shah
mesh_terms: D000222:Adaptation, Physiological; D000818:Animals; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000235:genetics / Q000378:metabolism; D051792:Basic Helix-Loop-Helix Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites; D018938:Caco-2 Cells; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism*; D047369:Chromatin Immunoprecipitation; D004195:Disease Models, Animal; D005260:Female; D017930:Genes, Reporter; D045325:HCT116 Cells; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000378:metabolism*; D007501:Iron / Q000097:blood; D000090463:Iron Deficiencies; D019189:Iron Metabolism Disorders / Q000235:genetics / Q000378:metabolism*; D019266:Iron, Dietary / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D011401:Promoter Regions, Genetic; D055550:Protein Stability; D013997:Time Factors; D014158:Transcription, Genetic; D014162:Transfection; D015854:Up-Regulation; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics / Q000378:metabolism; D000098742:Ferroportin; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D051792:Basic Helix-Loop-Helix Proteins; D027682:Cation Transport Proteins; D007501:Iron; D019266:Iron, Dietary; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D000098742:Ferroportin; D000099162:Endothelial PAS Domain-Containing Protein 1; C497397:Arnt protein, mouse; C494469:VHL protein, mouse