Dysregulated hepcidin response to dietary iron in male mice with reduced Gnpat expression
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Description
Exome sequencing has identified the glyceronephosphate O-acyltransferase (GNPAT) gene as a genetic modifier of iron overload in hereditary hemochromatosis (HH). Subjects with HFE (Homeostatic Iron Regulator) p.C282Y mutations and the GNPAT p.D519G variant had more iron loading compared with subjects without the GNPAT variant. In response to an oral iron challenge, women with GNPAT polymorphisms loaded more iron as compared with women without polymorphisms, reinforcing a role for GNPAT in iron homeostasis. The aim of the present study was to develop and characterize an animal model of disease to further our understanding of genetic modifiers, and in particular the role of GNPAT in iron homeostasis. We generated an Hfe/Gnpat mouse model reminiscent of the patients previously studied and studied these mice for up to 26 weeks. We also examined the effect of dietary iron loading on mice with reduced Gnpat expression. Gnpat heterozygosity in Hfe knockout mice does not play a role in systemic iron homeostasis; Gnpat+/- mice fed a high-iron diet, however, had lower hepatic hepcidin (HAMP) mRNA expression, whereas they have significantly higher serum iron levels and transferrin saturation compared with wildtype (WT) littermates on a similar diet. These results reinforce an independent role of GNPAT in systemic iron homeostasis, reproducing in an animal model, the observations in women with GNPAT polymorphisms subjected to an iron tolerance test.
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ID Code: | 205190 | ||||||
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Item Type: | Contribution to Journal (Journal Article) | ||||||
Refereed: | Yes | ||||||
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Measurements or Duration: | 12 pages | ||||||
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DOI: | 10.1042/BSR20201508 | ||||||
ISSN: | 0144-8463 | ||||||
Pure ID: | 68942447 | ||||||
Divisions: | Current > Research Centres > Centre for Genomics and Personalised Health Past > Institutes > Institute of Health and Biomedical Innovation Current > QUT Faculties and Divisions > Faculty of Health |
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Copyright Owner: | 2020 The Author(s) | ||||||
Copyright Statement: | This work is covered by copyright. Unless the document is being made available under a Creative Commons Licence, you must assume that re-use is limited to personal use and that permission from the copyright owner must be obtained for all other uses. If the document is available under a Creative Commons License (or other specified license) then refer to the Licence for details of permitted re-use. It is a condition of access that users recognise and abide by the legal requirements associated with these rights. If you believe that this work infringes copyright please provide details by email to qut.copyright@qut.edu.au | ||||||
Deposited On: | 07 Oct 2020 00:50 | ||||||
Last Modified: | 01 Mar 2024 08:08 |
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