Conditional deletion of ferritin H in mice induces loss of iron storage and liver damage
| Autor: | Larry Richman, Lukas C. Kühn, Deepak Darshan, Friedrich Beermann, Liviu Vanoaica |
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| Rok vydání: | 2009 |
| Předmět: |
Male
medicine.medical_specialty Iron macrophage Biology medicine.disease_cause Ferroxidase activity Mx-Cre Mice Hepcidins Hepcidin Internal medicine medicine Animals RNA Messenger Hemochromatosis Cell Death Hepatology medicine.diagnostic_test Transferrin saturation Liver Diseases targeted gene deletion Metabolism Embryo Mammalian medicine.disease Ferritin mouse embryonic fibroblast Endocrinology Liver Biochemistry Apoferritins hepcidin 1 Serum iron biology.protein Oxidative stress Antimicrobial Cationic Peptides |
| Zdroj: | Hepatology. 50:852-860 |
| ISSN: | 0270-9139 |
| DOI: | 10.1002/hep.23058 |
| Popis: | Ferritin plays a central role in iron metabolism by acting both as iron storage and a detoxifying protein. We generated a ferritin H allele with loxP sites and studied the conditional ferritin H deletion in adult mice. Ten days after Mx-Cre induced deletion, ferritin H messenger RNA (mRNA) was below 5% in the liver, spleen, and bone marrow of deleted mice compared to control littermates. Mice lost their cellular iron stores indicating the requirement of ferritin H in iron deposition. Serum iron and transferrin saturation were slightly increased and correlated with a two-fold increased liver hepcidin 1 mRNA and a reduced duodenal DcytB mRNA level. Under a normal iron regimen, deleted mice survived for 2 years without visible disadvantage. Mice fed on a high iron diet prior to ferritin H deletion suffered from severe liver damage. Similarly, ferritin H deleted mouse embryonic fibroblasts showed rapid cell death after exposure to iron salt in the medium. This was reversed by wild-type ferritin H but not by a ferritin H mutant lacking ferroxidase activity. Cell death was preceded by an increase in cytoplasmic free iron, reactive oxygen species, and mitochondrial depolarization. Conclusion: Our results provide evidence that the iron storage function of ferritin plays a major role in preventing iron-mediated cell and tissue damage. |
| Databáze: | OpenAIRE |
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