Hepcidin expression does not rescue the iron-poor phenotype of Kupffer cells in Hfe-null mice after liver transplantation.

Abstract

BACKGROUND & AIMS:

Hemochromatosis is a common hereditary disease caused by mutations in HFE and characterized by increased absorption of iron in the intestine. However, the intestine does not appear to be the site of mutant HFE activity in the disease; we investigated the role of the liver-the source of the iron regulatory hormone hepcidin-in pathogenesis in mice.

METHODS:

We exchanged livers between Hfe wild-type (+/+) and Hfe null (-/-) mice by orthotopic liver transplantation (OLT) and assessed histopathology, serum and tissue iron parameters, and hepatic hepcidin messenger RNA expression.

RESULTS:

At 6-8 months after OLT, Hfe(-/-) mice that received Hfe(-/-) livers maintained the hemochromatosis phenotype: iron accumulation in hepatocytes but not Kupffer cells (KC), increased transferrin levels, and low levels of iron in the spleen. Hfe(+/+) mice that received Hfe(-/-) livers had increased levels of iron in serum and liver and low levels of iron in spleen. However, they did not develop the iron-poor KCs that characterize hemochromatosis: KCs appeared iron rich, although hepatic hepcidin expression was low. Transplantation of Hfe(+/+) livers into Hfe(-/-) mice prevented hepatic iron accumulation but did not return spleen and plasma levels of iron to normal; KCs still appeared to be iron poor, despite normal hepcidin expression.

CONCLUSIONS:

In Hfe(-/-) mice, transplantation of livers from Hfe(+/+) mice reversed the iron-loading phenotype associated with hemochromatosis (regardless of Hfe expression in intestine). However, KCs still had low levels of iron that were not affected by hepatic hepcidin expression. These findings indicate an independent, iron-modifying effect of HFE in KCs.

• Authors: Cinzia Garuti, Yinghua Tian, Giuliana Montosi, Manuela Sabelli, Elena Corradini, Rolf Graf, Paolo Ventura, Alberto Vegetti, Pierre-Alain Clavien, Antonello Pietrangelo
• Journal: Gastroenterology (Gastroenterology) Vol. 139 Issue 1 Pg. 315-22.e1 (Jul 2010) ISSN: 1528-0012 [Electronic] United States
• PMID: 20338170 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.

Chemical References

• Antimicrobial Cationic Peptides
• Hamp protein, mouse
• Hemochromatosis Protein
• Hepcidins
• Hfe protein, mouse
• Histocompatibility Antigens Class I
• Membrane Proteins
• Iron

Topics

• Animals
• Antimicrobial Cationic Peptides (physiology)
• Hemochromatosis Protein
• Hepcidins
• Histocompatibility Antigens Class I (physiology)
• Iron (metabolism)
• Kupffer Cells (physiology)
• Liver (metabolism)
• Liver Transplantation
• Macrophages (physiology)
• Male
• Membrane Proteins (physiology)
• Mice
• Phenotype