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. Thirteen 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, by downregulating the iron transporter, Zip14.
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 cultured cells, primary hepatocyte culture, and mice.
Specific Aim 2 will determine the mechanism(s) by which HFE regulates the transport of iron into cells by the regulation of Zip14. 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 Northern European extraction. A single mutation in the HH protein, HFE, is responsible for 85% of the 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 #
5R37DK054488-12
Application #
8304865
Study Section
Integrative Nutrition and Metabolic Processes Study Section (INMP)
Program Officer
Wright, Daniel G
Project Start
2000-03-01
Project End
2015-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
12
Fiscal Year
2012
Total Cost
$370,311
Indirect Cost
$115,021
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
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