title: Pathways underlying iron accumulation in human nonalcoholic fatty liver disease.
abstract: BACKGROUND
  Mild iron overload is frequently observed in nonalcoholic fatty liver disease (NAFLD).
  
  
  OBJECTIVE
  We aimed to study putative pathways underlying iron accumulation in NAFLD.
  
  
  METHODS
  Hepatic and duodenal expression of critical iron molecules in NAFLD patients with (n = 32) and without (n = 29) iron overload, hereditary hemochromatosis (n = 10), and controls (n = 20) were investigated. Phlebotomy treatment was performed in 14 NAFLD patients.
  
  
  RESULTS
  The hepatic expressions of the iron-export protein ferroportin-1 (FP-1) and of the iron-sensing molecule hemojuvelin (HJV) were significantly lower in NAFLD patients. The mRNA expression of the iron-regulatory peptide hepcidin was increased in NAFLD patients with iron overload, which was paralleled by low duodenal FP-1 expression. Hepatic mRNA and serum protein concentrations of tumor necrosis factor-alpha (TNF-alpha) were increased in NAFLD patients and were inversely correlated with both liver FP-1 and HJV mRNA and positively associated with body mass index and hepatic hepcidin mRNA. Accordingly, TNF-alpha inhibited the FP-1 and HJV mRNA formation in HepG2 cells. Phlebotomy treatment of NALFD patients reduced serum ferritin, transferrin saturation, and TNF-alpha concentrations and improved liver function tests.
  
  
  CONCLUSIONS
  Iron accumulation in NAFLD may result from an impaired iron export due to down-regulation of FP1 and ineffective hepatic iron sensing, as indicated by low HJV expression. TNF-alpha appears to play a role in exerting these regulatory changes. Increased hepcidin formation in iron-overloaded NAFLD patients, however, results in decreased duodenal FP-1 expression, whereas a reduction in liver FP-1 may perpetuate hepatic iron retention. Phlebotomy offers a safe and efficient therapy for these metabolic disturbances.
authors.affiliation: Department of Internal Medicine, General Hospital Oberndorf, Oberndorf, Austria.
authors.forename: Elmar
authors.initials: E
authors.lastname: Aigner
authors.forename: Igor
authors.initials: I
authors.lastname: Theurl
authors.forename: Milan
authors.initials: M
authors.lastname: Theurl
authors.forename: Dieter
authors.initials: D
authors.lastname: Lederer
authors.forename: Heike
authors.initials: H
authors.lastname: Haufe
authors.forename: Otto
authors.initials: O
authors.lastname: Dietze
authors.forename: Michael
authors.initials: M
authors.lastname: Strasser
authors.forename: Christian
authors.initials: C
authors.lastname: Datz
authors.forename: Guenter
authors.initials: G
authors.lastname: Weiss
mesh_terms: D023181:Antimicrobial Cationic Peptides / Q000235:genetics / Q000378:metabolism*; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D004386:Duodenum / Q000378:metabolism; D005234:Fatty Liver / Q000378:metabolism* / Q000503:physiopathology / Q000628:therapy; D005260:Female; D058851:GPI-Linked Proteins; D015870:Gene Expression; D006432:Hemochromatosis / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology / Q000628:therapy; D000071020:Hemochromatosis Protein; D064451:Hepcidins; D006801:Humans; D007501:Iron / Q000378:metabolism*; D019190:Iron Overload / Q000209:etiology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D018962:Phlebotomy; D012333:RNA, Messenger / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000098742:Ferroportin
chemical_list: D023181:Antimicrobial Cationic Peptides; D027682:Cation Transport Proteins; D058851:GPI-Linked Proteins; C578702:HAMP protein, human; C481006:HJV protein, human; D000071020:Hemochromatosis Protein; D064451:Hepcidins; D008565:Membrane Proteins; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D000098742:Ferroportin; D007501:Iron