title: Copper availability contributes to iron perturbations in human nonalcoholic fatty liver disease.
abstract: OBJECTIVE
  Iron perturbations are frequently observed in nonalcoholic fatty liver disease (NAFLD). We aimed to investigate a potential association of copper status with disturbances of iron homeostasis in NAFLD.
  
  
  METHODS
  We retrospectively studied 140 NAFLD patients and 25 control subjects. Biochemical and hepatic iron and copper parameters were analyzed. Hepatic expression of iron regulatory molecules was investigated in liver biopsy specimens by reverse-transcription polymerase chain reaction and Western blot analysis.
  
  
  RESULTS
  NAFLD patients had lower hepatic copper concentrations than control subjects (21.9 +/- 9.8 vs 29.6 +/- 5.1 microg/g; P = .002). NAFLD patients with low serum and liver copper concentrations presented with higher serum ferritin levels (606.7 +/- 265.8 vs 224.2 +/- 176.0 mg/L; P < .001), increased prevalence of siderosis in liver biopsy specimens (36/46 vs 10/47 patients; P < .001), and with elevated hepatic iron concentrations (1184.4 +/- 842.7 vs 319.9 +/- 451.3 microg/g; P = .020). Lower serum concentrations of the copper-dependent ferroxidase ceruloplasmin (21.7 +/- 4.1 vs 30.4 +/- 6.4 mg/dL; P < .001) and decreased liver ferroportin (FP-1; P = .009) messenger RNA expression were found in these patients compared with NAFLD patients with high liver or serum copper concentrations. Accordingly, in rats, a reduced dietary copper intake was paralleled by a decreased hepatic FP-1 protein expression.
  
  
  CONCLUSIONS
  A significant proportion of NAFLD patients should be considered copper deficient. Our results indicate that copper status is linked to iron homeostasis in NAFLD, suggesting that low copper bioavailability causes increased hepatic iron stores via decreased FP-1 expression and ceruloplasmin ferroxidase activity thus blocking liver iron export in copper-deficient subjects.
authors.affiliation: General Hospital Oberndorf, Department of Internal Medicine, Oberndorf, Austria.
authors.forename: Elmar
authors.initials: E
authors.lastname: Aigner
authors.forename: Igor
authors.initials: I
authors.lastname: Theurl
authors.forename: Heike
authors.initials: H
authors.lastname: Haufe
authors.forename: Markus
authors.initials: M
authors.lastname: Seifert
authors.forename: Florian
authors.initials: F
authors.lastname: Hohla
authors.forename: Ludwig
authors.initials: L
authors.lastname: Scharinger
authors.forename: Felix
authors.initials: F
authors.lastname: Stickel
authors.forename: Frederic
authors.initials: F
authors.lastname: Mourlane
authors.forename: Günter
authors.initials: G
authors.lastname: Weiss
authors.forename: Christian
authors.initials: C
authors.lastname: Datz
mesh_terms: D000328:Adult; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000378:metabolism; D015153:Blotting, Western; D027682:Cation Transport Proteins / Q000378:metabolism; D002570:Ceruloplasmin / Q000378:metabolism; D003300:Copper / Q000097:blood / Q000172:deficiency / Q000378:metabolism*; D005260:Female; D005293:Ferritins / Q000097:blood; D058851:GPI-Linked Proteins; D000071020:Hemochromatosis Protein; D064451:Hepcidins; D006801:Humans; D007501:Iron / Q000097:blood / Q000378:metabolism*; D008099:Liver / Q000201:enzymology / Q000378:metabolism*; D008107:Liver Diseases / Q000150:complications / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D008875:Middle Aged; D051381:Rats; D017207:Rats, Sprague-Dawley; D012189:Retrospective Studies; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012806:Siderosis / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D000098742:Ferroportin
chemical_list: D023181:Antimicrobial Cationic Peptides; D027682:Cation Transport Proteins; D058851:GPI-Linked Proteins; D000071020:Hemochromatosis Protein; D064451:Hepcidins; C513726:Hjv protein, rat; D008565:Membrane Proteins; D000098742:Ferroportin; D003300:Copper; D005293:Ferritins; D007501:Iron; D002570:Ceruloplasmin