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Targeted gene disruption reveals an essential role for ceruloplasmin in cellular iron efflux
Open accessAbstract
Aceruloplasminemia is an autosomal recessive disorder of iron metabolism. Affected individuals evidence iron accumulation in tissue parenchyma in association with absent serum ceruloplasmin. Genetic studies of such patients reveal inherited mutations in the ceruloplasmin gene. To elucidate the role of ceruloplasmin in iron homeostasis, we created an animal model of aceruloplasminemia by disrupting the murine ceruloplasmin ( Cp ) gene. Although normal at birth, Cp −/− mice demonstrate progressive accumulation of iron such that by one year of age all animals have a prominent elevation in serum ferritin and a 3- to 6-fold increase in the iron content of the liver and spleen. Histological analysis of affected tissues in these mice shows abundant iron stores within reticuloendothelial cells and hepatocytes. Ferrokinetic studies in Cp +/+ and Cp −/− mice reveal equivalent rates of iron absorption and plasma iron turnover, suggesting that iron accumulation results from altered compartmentalization within the iron cycle. Consistent with this concept, Cp −/− mice showed no abnormalities in cellular iron uptake but a striking impairment in the movement of iron out of reticuloendothelial cells and hepatocytes. Our findings reveal an essential physiologic role for ceruloplasmin in determining the rate of iron efflux from cells with mobilizable iron stores.
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“Coexposure to iron and H2O2 were shown to enhance α-synuclein aggregation in vitro (126).”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [126]
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Metadata
- Authors
- Harris, Z. L., Durley, A. P., Man, T. K., & Gitlin, J. D.
- Affiliations
- Washington University in St. Louis (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 1999-09-14
- Volume
- 96
- Issue
- 19
- Pages
- 10812-10817
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC17965
- OpenAlex
- W2104657893
- Cited by
- 568
- References
- 40
- Citations by year
- 2026: 6 · 2025: 3 · 2024: 10 · 2023: 13 · 2022: 16 · 2021: 17 · 2020: 20 · 2019: 17 · 2018: 20 · 2017: 14 · 2016: 17 · 2015: 14 · 2014: 18 · 2013: 13 · 2012: 24
- FWCI
- 15.54
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (1p30hd033688-01, 5r01hl041536-13, 5k08dk002464-04, DK02464, HL41536)
- National Heart, Lung, and Blood Institute (HL41536)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK02464)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD 33688)
- Topics
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Life Sciences › Neuroscience › Neurology › Neurological diseases and metabolism
- Health Sciences › Nursing › Nutrition and Dietetics › Trace Elements in Health
- Keywords
- ceruloplasmin, aceruloplasminemia, iron efflux, cellular iron homeostasis, iron accumulation, iron metabolism, ferrokinetics, reticuloendothelial cells, hepatocytes, serum ferritin, iron storage
- MeSH terms
- Animals, Apoproteins, Ceruloplasmin, Disease Models, Animal, Homeostasis, Iron, Liver, Metal Metabolism, Inborn Errors, Models, Genetic, Phenotype, Spleen, Time Factors, Mutagenesis, Insertional, Neurodegenerative Diseases, Mice
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