Hereditary Hemochromatosis (HH) is the most common potentially fatal inherited disorder in people of Northern European origin. Approximately 85% of the cases result from a single base-pair mutation, which converts Cys to Tyr in the HFE protein. This mutation causes a recessive disease resulting in increased iron absorption and accumulation of iron in selected tissues. The iron overload damages these organs leading to cirrhosis of the liver, diabetes, cardiomyopathy, and arthritis. Eighteen years after the cloning and identification of HFE, the mechanisms by which HFE affect iron-homeostasis remain to be determined. We hypothesize that HFE has at least two functions. It lowers iron uptake into the body, globally, by increasing the transcription of hepcidin, a hormone that negatively regulates iron efflux out of intestinal epithelial cells into the blood. HFE also negatively regulates the iron levels in the cell, locally.
Specific Aim 1 will determine the mechanism(s) by which transferrin mediates the HFE-dependent regulation of hepcidin. Several models of how HFE increases hepcidin transcription will be tested in primary hepatocyte culture, and mice.
Specific Aim 2 will determine the mechanism(s) by which HFE regulates the transport of iron into cells. The long-term goal of this work is to understand the function of HFE.

Public Health Relevance

Hereditary hemochromatosis (HH) is the most common potentially lethal inherited disease in people of N. European extraction. A single mutation in the HH protein, HFE, is responsible for 85% of cases of HH. Excess iron in tissues results in cirrhosis of the liver, increased risk of liver cancer, diabetes, heart arythmias and arthritis, usually by the fifth decade of life. In this application, we seek to define the function of HFE.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
4R37DK054488-15
Application #
9057771
Study Section
Special Emphasis Panel (NSS)
Program Officer
Roy, Cindy
Project Start
2000-03-01
Project End
2020-04-30
Budget Start
2015-07-01
Budget End
2016-04-30
Support Year
15
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Oregon Health and Science University
Department
Type
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
Wahedi, Mastura; Wortham, Aaron M; Kleven, Mark D et al. (2017) Matriptase-2 suppresses hepcidin expression by cleaving multiple components of the hepcidin induction pathway. J Biol Chem 292:18354-18371
Zane, Hannah K; Doh, Julia K; Enns, Caroline A et al. (2017) Versatile Interacting Peptide (VIP) Tags for Labeling Proteins with Bright Chemical Reporters. Chembiochem 18:470-474
Zhao, Ningning; Zhang, An-Sheng; Wortham, Aaron M et al. (2017) The Tumor Suppressor, P53, Decreases the Metal Transporter, ZIP14. Nutrients 9:
Tuschl, Karin; Meyer, Esther; Valdivia, Leonardo E et al. (2016) Mutations in SLC39A14 disrupt manganese homeostasis and cause childhood-onset parkinsonism-dystonia. Nat Commun 7:11601
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
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
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; 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
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
Yabu, Julie M; Anderson, Matthew W; Kim, Deborah et al. (2013) Sensitization from transfusion in patients awaiting primary kidney transplant. Nephrol Dial Transplant 28:2908-18

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