Hereditary hemochromatosis (HH) is the most common inherited disorder in people of Northern European origin. Iron overload results in damage specific organs leading to cirrhosis of the liver, liver cancer, diabetes, cardiomyopathy, and arthritis. The liver is a major iron-sensing organ in the body. Transferrin is the major iron transport protein in the blood. Mutations in transferrin receptor 2 (TfR2), which is predominantly expressed in hepatocytes and erythrocyte precursors result in HH. Tfr2 forms a complex with HFE, another protein involved in iron homeostasis. Experiments described in this proposal will test the model that the TfR2-HFE complex provides a sensing mechanism to detect iron-loaded Tf and thereby regulates the transcription of hepcidin, a peptide hormone that negatively regulates the efflux of iron out of intestinal cells and macrophages. Alternatively, the TfR2-HFE complex could establish basal levels of hepcidin transcription. Other proteins involved in the complex and in signaling mechanisms will be identified. The long-term goal of this research is to understand how mutations in key proteins disturb the iron balance in the body to reveal the mechanisms by which the body regulates iron-homeostasis.

Public Health Relevance

The uptake of iron into the body is tightly controlled. Too little iron causes anemia and compromised brain development. Complications of too much iron include liver cirrhosis, liver cancer, heart arrythmias, and arthritis. This project seeks to understand how the body senses and regulates iron-uptake.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK072166-06A1
Application #
8504642
Study Section
Molecular and Cellular Hematology (MCH)
Program Officer
Bishop, Terry Rogers
Project Start
2005-07-01
Project End
2018-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
6
Fiscal Year
2013
Total Cost
$393,265
Indirect Cost
$137,898
Name
Oregon Health and Science University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
Zhao, Ningning; Maxson, Julia E; Zhang, Richard H et al. (2016) Neogenin Facilitates the Induction of Hepcidin Expression by Hemojuvelin in the Liver. J Biol Chem 291:12322-35
Chen, Juxing; Enns, Caroline A (2015) CD81 promotes both the degradation of transferrin receptor 2 (TfR2) and the Tfr2-mediated maintenance of hepcidin expression. J Biol Chem 290:7841-50
Zhao, Ningning; Nizzi, Christopher P; Anderson, Sheila A et al. (2015) Low intracellular iron increases the stability of matriptase-2. J Biol Chem 290:4432-46
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
Worthen, Christal A; Enns, Caroline A (2014) The role of hepatic transferrin receptor 2 in the regulation of iron homeostasis in the body. Front Pharmacol 5:34
Zhao, Ningning; Enns, Caroline A (2013) N-linked glycosylation is required for transferrin-induced stabilization of transferrin receptor 2, but not for transferrin binding or trafficking to the cell surface. Biochemistry 52:3310-9
Zhao, Ningning; Zhang, An-Sheng; Enns, Caroline A (2013) Iron regulation by hepcidin. J Clin Invest 123:2337-43
Wang, Jinzhi; Chen, Juxing; Enns, Caroline A et al. (2013) The first transmembrane domain of lipid phosphatase SAC1 promotes Golgi localization. PLoS One 8:e71112
Byrne, Shaina L; Buckett, Peter D; Kim, Jonghan et al. (2013) Ferristatin II promotes degradation of transferrin receptor-1 in vitro and in vivo. PLoS One 8:e70199
Enns, Caroline A; Ahmed, Riffat; Wang, Jiaohong et al. (2013) Increased iron loading induces Bmp6 expression in the non-parenchymal cells of the liver independent of the BMP-signaling pathway. PLoS One 8:e60534

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