Ceruloplasmin deficiency does not induce macrophagic iron overload: Lessons from a new rat model of hereditary aceruloplasminemia

Journal article


Kenawi, Moussa, Rouger, Emmanuel, Island, Marie-Laure, Leroyer, Patricia, Robin, François, Rémy, Séverine, Tesson, Laurent, Anegon, Ignacio, Nay, Kevin, Derbré, Frédéric, Brissot, Pierre, Ropert, Martine, Cavey, Thibault and Loréal, Olivier. (2019). Ceruloplasmin deficiency does not induce macrophagic iron overload: Lessons from a new rat model of hereditary aceruloplasminemia. The FASEB Journal. 33(12), pp. 13492 - 13502. https://doi.org/10.1096/fj.201901106R
AuthorsKenawi, Moussa, Rouger, Emmanuel, Island, Marie-Laure, Leroyer, Patricia, Robin, François, Rémy, Séverine, Tesson, Laurent, Anegon, Ignacio, Nay, Kevin, Derbré, Frédéric, Brissot, Pierre, Ropert, Martine, Cavey, Thibault and Loréal, Olivier
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.

Keywordshepcidin; CRISPR/Cas9; genetic disease; metals; hepatocyte
Year2019
JournalThe FASEB Journal
Journal citation33 (12), pp. 13492 - 13502
PublisherFederation of American Societies for Experimental Biology
ISSN1530-6860
Digital Object Identifier (DOI)https://doi.org/10.1096/fj.201901106R
Scopus EID2-s2.0-85075959938
Page range13492 - 13502
Research GroupMary MacKillop Institute for Health Research
Publisher's version
File Access Level
Controlled
Place of publicationUnited States of America
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