Resistance of ferroportin to hepcidin binding causes exocrine pancreatic failure and fatal iron overload.

Abstract

The regulatory axis between the iron hormone hepcidin and its receptor, the iron exporter ferroportin (FPN), is central to iron homeostasis. Mutations preventing hepcidin-mediated degradation of FPN cause systemic iron overload. We have introduced a point mutation (C326S) into the murine Fpn locus, resembling human hereditary hemochromatosis type 4, including elevated plasma iron and ferritin levels, high transferrin saturation, hepatic iron overload, and iron depletion of duodenal enterocytes and reticuloendothelial macrophages. Unlike other mouse models of iron overload, homozygous C326S mice die between 7 and 14 months of age. Pancreatic acinar cells display marked iron accumulation, oxidative damage and degeneration, associated with failure of the exocrine pancreas and severe body weight loss. Rescue experiments reveal iron overload and exocrine pancreatic failure as leading causes of death. This work uncovers the critical importance of the hepcidin-ferroportin regulatory axis for life and unveils the sensitivity of the exocrine pancreas to iron overload.

• Authors: Sandro Altamura, Regina Kessler, Hermann-Josef Gröne, Norbert Gretz, Matthias W Hentze, Bruno Galy, Martina U Muckenthaler
• Journal: Cell metabolism (Cell Metab) Vol. 20 Issue 2 Pg. 359-67 (Aug 05 2014) ISSN: 1932-7420 [Electronic] United States
• PMID: 25100063 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Inc. All rights reserved.

Chemical References

• Cation Transport Proteins
• Hepcidins
• metal transporting protein 1
• Iron

Topics

• Acinar Cells (cytology, metabolism)
• Animals
• Cation Transport Proteins (chemistry, genetics, metabolism)
• Disease Models, Animal
• Gene Knock-In Techniques
• Hepcidins (chemistry, metabolism)
• Homozygote
• Iron (metabolism)
• Iron Overload (etiology, metabolism, pathology)
• Mice
• Mice, Inbred C57BL
• Oxidative Stress
• Pancreatic Diseases (etiology, metabolism, pathology)
• Protein Binding