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Ceruloplasmin deficiency does not induce macrophagic iron overload: Lessons from a new rat model of hereditary aceruloplasminemia
Kenawi, Moussa Rouger, Emmanuel Island, Marie-Laure Leroyer, Patricia Robin, François Rémy, Séverine Tesson, Laurent Anegon, Ignacio Nay, Kevin Derbré, Frédéric
Kenawi, Moussa
Rouger, Emmanuel
Island, Marie-Laure
Leroyer, Patricia
Robin, François
Rémy, Séverine
Tesson, Laurent
Anegon, Ignacio
Nay, Kevin
Derbré, Frédéric
Abstract
Hereditary aceruloplasminemia (HA), related to mutations in the ceruloplasmin (Cp) gene, leads to iron accumulation. Ceruloplasmin ferroxidase activity being considered essential for macrophage iron release, macrophage iron overload is expected, but it is not found in hepatic and splenic macrophages in humans. Our objective was to get a better understanding of the mechanisms leading to iron excess in HA. A clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR associated protein 9 (Cas9) knockout of the Cp gene was performed on Sprague‐Dawley rats. We evaluated the iron status in plasma, the expression of iron metabolism genes, and the status of other metals whose interactions with iron are increasingly recognized. In Cp–/– rats, plasma ceruloplasmin and ferroxidase activity were absent, together with decreased iron concentration and transferrin saturation. Similarly as in humans, the hepatocytes were iron overloaded conversely to hepatic and splenic macrophages. Despite a relative hepcidin deficiency in Cp–/– rats and the loss of ferroxidase activity, potentially expected to limit the interaction of iron with transferrin, no increase of plasma non‐transferrin‐bound iron level was found. Copper was decreased in the spleen, whereas manganese was increased in the plasma. These data suggest that the reported role of ceruloplasmin cannot fully explain the iron hepatosplenic phenotype in HA, encouraging the search for additional mechanisms.
Keywords
hepcidin, CRISPR/Cas9, genetic disease, metals, hepatocyte
Date
2019
Type
Journal article
Journal
The FASEB Journal
Book
Volume
33
Issue
12
Page Range
13492-13502
Article Number
ACU Department
Mary MacKillop Institute for Health Research
Faculty of Health Sciences
Faculty of Health Sciences
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Relation URI
Source URL
Event URL
Open Access Status
License
File Access
Controlled