Although disorders of iron metabolism such as iron deficiency and iron overload are common in humans, our understanding of the proteins that mediate iron uptake into cells remains incomplete. In the first cycle of this grant, we established that the transmembrane protein ZIP14, a member of the ZIP family of metal-ion transporters, could transport iron into cells and is up-regulated by iron overload in the liver and pancreas, tissues that are particularly susceptible to iron-related pathologies. A direct role for ZIP14 in ion metabolism in vivo has been revealed by our recent studies of ZIP14 knockout mice, which display alterations in iron status parameters and a marked impairment in the uptake of non-transferrin-bound iron by the liver and pancreas. By screening other ZIP family members for iron transport activity, we recently discovered that ZIP8, the most closely related protein to ZIP14, could also transport iron and is up-regulated by cellular iron loading. In the next funding cycle, we will define the physiologic roles of ZIP14 and ZIP8 in iron metabolism. Our central hypothesis is that ZIP14 and ZIP8 participate in iron uptake by various tissues, including those that accumulate iron during iron overload.
The first aim of the proposed research will define the role of ZIP14 in tissue iron loading by using ZIP14 knockout mice intercrossed with Hfe and Hjv knockout mice, mouse models of the human iron overload disorders, hereditary hemochromatosis and juvenile hemochromatosis, respectively. In our second aim, we will determine the mechanism of impaired hepatic iron loading in double-knockout ZIP14;Hfe mice by examining hepatic uptake of non-transferrin-bound iron and transferrin-bound iron. In our third aim, we will elucidate the role(s) of ZIP8 in iron metabolism and the contribution of ZIP8 to iron loading of the pancreas and heart by using novel tissue-specific ZIP8 knockout mice. The work proposed in these aims will help to close the gap in our mechanistic understanding of how tissues take up iron. Such results are expected to have a positive impact because they may identify new therapeutic targets for treating disorders of iron metabolism and their associated pathologies.

Public Health Relevance

Iron overload is increasingly being recognized as a public health concern. This project aims to elucidate the proteins responsible for iron uptake by various organs, particularly those adversely affected by iron overload. It is hoped that this work will lea to the identification of therapeutic targets for preventing/treating iron overload.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Integrative Nutrition and Metabolic Processes Study Section (INMP)
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Bishop, Terry Rogers
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University of Florida
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Coffey, Richard; Knutson, Mitchell D (2017) The plasma membrane metal-ion transporter ZIP14 contributes to nontransferrin-bound iron uptake by human ?-cells. Am J Physiol Cell Physiol 312:C169-C175
Yang, Xiaoyan; Park, Seong-Hoon; Chang, Hsiang-Chun et al. (2017) Sirtuin 2 regulates cellular iron homeostasis via deacetylation of transcription factor NRF2. J Clin Invest 127:1505-1516
Jenkitkasemwong, Supak; Wang, Chia-Yu; Knutson, Mitchell D (2016) Measurement of Transferrin- and Non-transferrin-bound Iron Uptake by Mouse Tissues. Bio Protoc 6:
Jenkitkasemwong, Supak; Wang, Chia-Yu; Coffey, Richard et al. (2015) SLC39A14 Is Required for the Development of Hepatocellular Iron Overload in Murine Models of Hereditary Hemochromatosis. Cell Metab 22:138-50
Zhao, Ningning; Zhang, An-Sheng; Worthen, Christal et al. (2014) An iron-regulated and glycosylation-dependent proteasomal degradation pathway for the plasma membrane metal transporter ZIP14. Proc Natl Acad Sci U S A 111:9175-80
Coffey, Richard; Nam, Hyeyoung; Knutson, Mitchell D (2014) Microarray analysis of rat pancreas reveals altered expression of Alox15 and regenerating islet-derived genes in response to iron deficiency and overload. PLoS One 9:e86019
Nam, Hyeyoung; Wang, Chia-Yu; Zhang, Lin et al. (2013) ZIP14 and DMT1 in the liver, pancreas, and heart are differentially regulated by iron deficiency and overload: implications for tissue iron uptake in iron-related disorders. Haematologica 98:1049-57
Wang, Chia-Yu; Knutson, Mitchell D (2013) Hepatocyte divalent metal-ion transporter-1 is dispensable for hepatic iron accumulation and non-transferrin-bound iron uptake in mice. Hepatology 58:788-98
Wang, Chia-Yu; Jenkitkasemwong, Supak; Duarte, Stephanie et al. (2012) ZIP8 is an iron and zinc transporter whose cell-surface expression is up-regulated by cellular iron loading. J Biol Chem 287:34032-43
Jenkitkasemwong, Supak; Wang, Chia-Yu; Mackenzie, Bryan et al. (2012) Physiologic implications of metal-ion transport by ZIP14 and ZIP8. Biometals 25:643-55

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