SLC39A14 Is Required for the Development of Hepatocellular Iron Overload in Murine Models of Hereditary Hemochromatosis
Open accessAbstract
Nearly all forms of hereditary hemochromatosis are characterized by pathological iron accumulation in the liver, pancreas, and heart. These tissues preferentially load iron because they take up non-transferrin-bound iron (NTBI), which appears in the plasma during iron overload. Yet, how tissues take up NTBI is largely unknown. We report that ablation of Slc39a14, the gene coding for solute carrier SLC39A14 (also called ZIP14), in mice markedly reduced the uptake of plasma NTBI by the liver and pancreas. To test the role of SLC39A14 in tissue iron loading, we crossed Slc39a14(-/-) mice with Hfe(-/-) and Hfe2(-/-) mice, animal models of type 1 and type 2 (juvenile) hemochromatosis, respectively. Slc39a14 deficiency in hemochromatotic mice greatly diminished iron loading of the liver and prevented iron deposition in hepatocytes and pancreatic acinar cells. The data suggest that inhibition of SLC39A14 may mitigate hepatic and pancreatic iron loading and associated pathologies in iron overload disorders.
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The clinical severity of hemochromatosis is related to NTBI, a toxic iron species bound to low molecular weight molecules, easily taken up by hepatocytes and pancreatic cells via ZIP14 transporter and by cardiomyocytes through other transporters.
“The clinical severity of hemochromatosis is related to NTBI, a toxic iron species bound to low molecular weight molecules, easily taken up by hepatocytes and pancreatic cells via ZIP14 transporter82 and by cardiomyocytes through other transporters.83”
From Iron metabolism and iron disorders revisited in the hepcidin era (2020) · cites this paper as [82]
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- Authors
- Jenkitkasemwong, S., Wang, C.-Y., Coffey, R., Zhang, W., Chan, A., Biel, T., Kim, J.-S., Hojyo, S., Fukada, T., & Knutson, M. D.
- Affiliations
- University of Florida (US)
- German Rheumatism Research Centre (DE)
- SHOWA Medical University (JP)
- Corresponding author
- Knutson, Mitchell D.
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2015-07
- Volume
- 22
- Issue
- 1
- Pages
- 138-150
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC4497937
- OpenAlex
- W1564878813
- Cited by
- 245
- References
- 8
- Citations by year
- 2026: 19 · 2025: 28 · 2024: 30 · 2023: 16 · 2022: 27 · 2021: 20 · 2020: 15 · 2019: 21 · 2018: 18 · 2017: 31 · 2016: 17 · 2015: 2
- FWCI
- 17.82
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- Japan Society for the Promotion of Science (26462324)
- National Institute on Aging (AG028740, P30AG028740)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK 080706, DK079879, R01DK090115, DK090115, R01DK079879, R01DK080706)
- Topics
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Health Sciences › Nursing › Nutrition and Dietetics › Trace Elements in Health
- Life Sciences › Neuroscience › Neurology › Neurological diseases and metabolism
- Keywords
- SLC39A14, ZIP14, hereditary hemochromatosis, non-transferrin-bound iron, iron absorption, HFE gene, iron overload
- MeSH terms
- Animals, Cells, Cultured, Female, Hemochromatosis, Liver, Male, Mice, Inbred C57BL, Pancreas, Gene Deletion, Iron Overload, Hepatocytes, Cation Transport Proteins
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