Copper availability contributes to iron perturbations in human nonalcoholic fatty liver disease

Gastroenterology. 2008 Aug;135(2):680-8. doi: 10.1053/j.gastro.2008.04.007. Epub 2008 Apr 15.

Abstract

Background & aims: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Antimicrobial Cationic Peptides / metabolism
  • Blotting, Western
  • Cation Transport Proteins / metabolism
  • Ceruloplasmin / metabolism
  • Copper / blood
  • Copper / deficiency
  • Copper / metabolism*
  • Female
  • Ferritins / blood
  • GPI-Linked Proteins
  • Hemochromatosis Protein
  • Hepcidins
  • Humans
  • Iron / blood
  • Iron / metabolism*
  • Liver / enzymology
  • Liver / metabolism*
  • Liver Diseases / complications
  • Liver Diseases / genetics
  • Liver Diseases / metabolism*
  • Male
  • Membrane Proteins / metabolism
  • Middle Aged
  • Rats
  • Rats, Sprague-Dawley
  • Retrospective Studies
  • Reverse Transcriptase Polymerase Chain Reaction
  • Siderosis / etiology*
  • Siderosis / genetics
  • Siderosis / metabolism

Substances

  • Antimicrobial Cationic Peptides
  • Cation Transport Proteins
  • GPI-Linked Proteins
  • Hemochromatosis Protein
  • Hepcidins
  • Hjv protein, rat
  • Membrane Proteins
  • metal transporting protein 1
  • Copper
  • Ferritins
  • Iron
  • Ceruloplasmin