Functional iron deficiency in toxic milk mutant mice (tx-J) despite high hepatic ferroportin: a critical role of decreased GPI-ceruloplasmin expression in liver macrophages

Functional iron deficiency in toxic milk mutant mice (tx-J) despite high hepatic ferroportin: a critical role of decreased GPI-ceruloplasmin expression in liver macrophages

Jackson toxic milk mutant mice (tx-J) carrying a missense mutation in the Atp7b gene are animal models of the Wilson disease. In both the Wilson patients and the tx-J mice, mutations in the ATP7B/Atp7b gene lead to disturbances in copper metabolism. The dysfunction of ATP7B/Atp7b leads to a reductio...

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Bibliographic Details
Published in:Metallomics Vol. 11; no. 6; pp. 179 - 192
Main Authors: Jo czy, Aneta, Lipi ski, Pawe, Ogórek, Mateusz, Starzy ski, Rafa Rados aw, Krzysztofik, Daria, Bednarz, Aleksandra, Krzeptowski, Wojciech, Szudzik, Mateusz, Haberkiewicz, Olga, Mi o, Agnieszka, Grzmil, Pawe, Lenartowicz, Ma gorzata
Format: Journal Article
Language:English
Published: England Royal Society of Chemistry 19-06-2019
Subjects:
Accumulation
Anemia
Animal models
ATP7B gene
Bile
Ceruloplasmin
Copper
Disturbances
Efflux
Ferroxidase
Hepatocytes
Hepcidin
Internalization
Iron
Iron deficiency
Liver
Macrophages
Metabolism
Mice
Missense mutation
Mutants
Mutation
Nutrient deficiency
Wilson's disease
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Summary:Jackson toxic milk mutant mice (tx-J) carrying a missense mutation in the Atp7b gene are animal models of the Wilson disease. In both the Wilson patients and the tx-J mice, mutations in the ATP7B/Atp7b gene lead to disturbances in copper metabolism. The dysfunction of ATP7B/Atp7b leads to a reduction in the incorporation of copper into apoceruloplasmin; this decreases the ferroxidase activity of ceruloplasmin necessary for the efflux of iron from cells and reduces the release of copper from hepatocytes to the bile; this results in a massive hepatic copper accumulation. A decrease in the ferroxidase activity of ceruloplasmin in the tx-J mice emphasises the practicality of this animal model for the exploration of disturbances in iron balance triggered by dysregulation of copper metabolism. We found that 6-month-old tx-J mutants developed mild anaemia caused by functional iron deficiency. The tx-J mutants showed decreased plasma iron levels with concomitant iron accumulation in hepatocytes and liver macrophages. Hepatic iron retention was accompanied by decreased expression of the membrane form of ceruloplasmin in both liver cell types. Interestingly, in the liver of mutants, we found high levels of ferroportin (an iron exporter) on the surface of liver macrophages despite increased hepatic expression of hepcidin, a peptide inducing internalization and degradation of ferroportin. We conclude that even when the ferroportin expression is high, ceruloplasmin remains a limiting factor in the release of iron to the extracellular environment. Jackson toxic milk mutant mice (tx-J) carrying a missense mutation in the Atp7b gene are animal models of the Wilson disease.
Bibliography:Electronic supplementary information (ESI) available. See DOI
10.1039/c9mt00035f
ISSN:1756-5901
1756-591X
DOI:10.1039/c9mt00035f