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.

DESIGN:

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: Elmar Aigner, Igor Theurl, Milan Theurl, Dieter Lederer, Heike Haufe, Otto Dietze, Michael Strasser, Christian Datz, Guenter Weiss
• Journal: The American journal of clinical nutrition (Am J Clin Nutr) Vol. 87 Issue 5 Pg. 1374-83 (May 2008) ISSN: 1938-3207 [Electronic] United States
• PMID: 18469261 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antimicrobial Cationic Peptides
• Cation Transport Proteins
• GPI-Linked Proteins
• HAMP protein, human
• HJV protein, human
• Hemochromatosis Protein
• Hepcidins
• Membrane Proteins
• RNA, Messenger
• Tumor Necrosis Factor-alpha
• metal transporting protein 1
• Iron

Topics

• Antimicrobial Cationic Peptides (genetics, metabolism)
• Cation Transport Proteins (genetics, metabolism)
• Down-Regulation
• Duodenum (metabolism)
• Fatty Liver (metabolism, physiopathology, therapy)
• Female
• GPI-Linked Proteins
• Gene Expression
• Hemochromatosis (genetics, metabolism, physiopathology, therapy)
• Hemochromatosis Protein
• Hepcidins
• Humans
• Iron (metabolism)
• Iron Overload (etiology)
• Male
• Membrane Proteins (genetics, metabolism)
• Middle Aged
• Phlebotomy
• RNA, Messenger (metabolism)
• Tumor Necrosis Factor-alpha (metabolism)