title: Disrupted hepcidin regulation in HFE-associated haemochromatosis and the liver as a regulator of body iron homoeostasis.
abstract: BACKGROUND
  The mechanisms responsible for disturbed iron homoeostasis in hereditary haemochromatosis are poorly understood. However, results of some studies indicate a link between hepcidin, a liver-derived peptide, and intestinal iron absorption, suggesting that this molecule could play a part in hepatic iron overload. To investigate this possible association, we studied the hepatic expression of the gene for hepcidin (HAMP) and a gene important in iron transport (IREG1) in patients with haemochromatosis, in normal controls, and in Hfe-knockout mice.
  
  
  METHODS
  We extracted total RNA from the liver tissue of 27 patients with HFE-associated haemochromatosis, seven transplant donors (controls), and Hfe-knockout mice. HAMP and IREG1 mRNA concentrations were examined by ribonuclease protection assays and expressed relative to the housekeeping gene GAPD.
  
  
  RESULTS
  There was a significant decrease in HAMP expression in untreated patients compared with controls (5.4-fold, 95% CI 3.3-7.5; p<0.0001) despite significantly increased iron loading. Similarly, we noted a decrease in Hamp expression in iron-loaded Hfe-knockout mice. Hepatic IREG1 expression was greatly upregulated in patients with haemochromatosis (1.8-fold, 95% CI 1.5-2.2; p=0.002). There was a significant correlation between hepatic iron concentration and expression of HAMP (r=0.59, p=0.02) and IREG1 (r=0.67, p=0.007) in untreated patients.
  
  
  CONCLUSIONS
  Lack of HAMP upregulation in HFE-associated haemochromatosis despite significant hepatic iron loading indicates that HFE plays an important part in the regulation of hepcidin expression in response to iron overload. Our results imply that the liver is important in the pathophysiology of HFE-associated haemochromatosis. Furthermore, the increase in hepatic IREG1 expression in haemochromatosis suggests that IREG1 could function to facilitate the removal of excess iron from the liver.
authors.affiliation: Hepatic Fibrosis Group, Queensland Institute of Medical Research, Royal Brisbane Hospital, Queensland, Herston, Australia.
authors.forename: Kim R
authors.initials: KR
authors.lastname: Bridle
authors.forename: David M
authors.initials: DM
authors.lastname: Frazer
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Wilkins
authors.forename: Jeanette L
authors.initials: JL
authors.lastname: Dixon
authors.forename: David M
authors.initials: DM
authors.lastname: Purdie
authors.forename: Darrell H G
authors.initials: DH
authors.lastname: Crawford
authors.forename: V Nathan
authors.initials: VN
authors.lastname: Subramaniam
authors.forename: Lawrie W
authors.initials: LW
authors.lastname: Powell
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Anderson
authors.forename: Grant A
authors.initials: GA
authors.lastname: Ramm
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D027682:Cation Transport Proteins / Q000502:physiology*; D005260:Female; D006432:Hemochromatosis / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D000071020:Hemochromatosis Protein; D064451:Hepcidins; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D006706:Homeostasis; D006801:Humans; D007501:Iron / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008875:Middle Aged; D000098742:Ferroportin
chemical_list: D023181:Antimicrobial Cationic Peptides; D027682:Cation Transport Proteins; C578702:HAMP protein, human; C103673:HFE protein, human; C579599:Hamp protein, mouse; D000071020:Hemochromatosis Protein; D064451:Hepcidins; C499535:Hfe protein, mouse; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; D000098742:Ferroportin; D007501:Iron