title: Iron stores modulate hepatic hepcidin expression by an HFE-independent pathway.
abstract: OBJECTIVE
  In HFE-related hereditary hemochromatosis an inappropriately low hepatic expression of the iron-regulatory peptide hepcidin (encoded by HAMP) has been suggested to cause iron overload. The aim of the present study was to evaluate whether the hepatic expression of HAMP in relation to iron stores requires HFE or might involve other important iron-related genes including HJV (encoding hemojuvelin) and TFR2 (encoding transferrin receptor-2).
  
  
  METHODS
  Using quantitative RT-PCR, the iron-dependent hepatic expression patterns of HAMP, HJV, and TFR2 were evaluated in human and murine HFE-related hemochromatosis.
  
  
  RESULTS
  The overall level of hepatic HAMP expression in human and murine HFE-related hemochromatosis is impaired but can still be modulated by iron stores. Moreover, we demonstrate an HFE-independent correlation between the expression of HAMP and TFR2 in mouse and human livers. On the other hand, a strong correlation between the hepatic expression of HAMP and HJV was only found in hemochromatosis patients and Hfe-deficient mice.
  
  
  CONCLUSIONS
  The central pathogenetic step in HFE-related hemochromatosis is an impaired basal expression of HAMP rather than a lack of HAMP upregulation in response to iron stores. An HFE-independent pathway that seems to involve TFR2 and HJV can regulate HAMP expression under conditions of iron overload.
authors.affiliation: Department of Internal Medicine IV, University Hospital Heidelberg, Im Neuenheimer Feld 410, DE-69120 Heidelberg, Germany.
authors.forename: Sven G
authors.initials: SG
authors.lastname: Gehrke
authors.forename: Thomas
authors.initials: T
authors.lastname: Herrmann
authors.forename: Hasan
authors.initials: H
authors.lastname: Kulaksiz
authors.forename: Uta
authors.initials: U
authors.lastname: Merle
authors.forename: Karin
authors.initials: K
authors.lastname: Bents
authors.forename: Iris
authors.initials: I
authors.lastname: Kaiser
authors.forename: Hans-Dieter
authors.initials: HD
authors.lastname: Riedel
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Stremmel
mesh_terms: D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000096:biosynthesis* / Q000502:physiology; D058851:GPI-Linked Proteins; D020869:Gene Expression Profiling; D006432:Hemochromatosis / Q000235:genetics / Q000503:physiopathology*; D000071020:Hemochromatosis Protein; D064451:Hepcidins; D015395:Histocompatibility Antigens Class I / Q000502:physiology*; D006801:Humans; D007501:Iron / Q000378:metabolism*; D019190:Iron Overload / Q000235:genetics* / Q000503:physiopathology; D008099:Liver / Q000502:physiology; D008565:Membrane Proteins / Q000096:biosynthesis / Q000502:physiology*; D051379:Mice; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation
chemical_list: D023181:Antimicrobial Cationic Peptides; D058851:GPI-Linked Proteins; C578702:HAMP protein, human; C103673:HFE protein, human; C481006:HJV protein, human; C579599:Hamp protein, mouse; D000071020:Hemochromatosis Protein; D064451:Hepcidins; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; D007501:Iron