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How is hepcidin expression regulated by polyphenols?

Reference	BB/H003576/1
Principal Investigator / Supervisor	Professor Surjit Srai
Co-Investigators / Co-Supervisors
Institution	University College London
Department	Structural Molecular Biology
Funding type	Research
Value (£)	417,392
Status	Completed
Type	Research Grant
Start date	11/01/2010
End date	10/07/2013
Duration	42 months

Abstract

Hepcidin through its control of iron flux is now regarded as the central regulator of body iron homeostasis. Hepcidin expression is influenced by the rate of erythropoiesis, iron stores, inflammation, hypoxia and oxidative stress. These stimuli control hepcidin by interacting with hepatocyte cell surface proteins including hemojuvelin, Hfe, transferrin receptor 2, IL-R and TMPRSS6 through various transduction pathways which result in cognate transcription factors binding to response elements such as c/EBPa, JAK-STAT3, USF1, BMP-SMAD found in the hepcidin promoter. Work in our laboratory has found that in addition to systemic stimuli, hepcidin expression may also be modulated by dietary polyphenols. This induction paralleled the activation of phase cytoprotective genes such as glutathione S-transferase and quinone reductase. Although it is possible that these molecules may share the same mechanism of induction, the precise pathway for polyphenol-induced hepcidin expression is not known. In this application, a number of complementary approaches will be used to examine hepcidin regulation both in vitro ( Huh7 cells transfected with promoter -reporter construct treated with polyphenols), and in vivo by feeding animals with these compounds. In vitro studies will allow us to determine transduction molecules and promoter response elements involved in modulating hepcidin in response to treatment with hepcidin and its metabolites. Since hepcidin expression has an inverse relationship with iron absorption, intestinal iron absorption together with serum and tissue iron levels and cell surface proteins will be determined in vivo studies. This will allow us to equate the effect of polyphenols on hepcidin and iron balance. This will also allow us to recognise cell surface proteins involved

Summary

Iron deficiency anaemia is the most frequent nutritional deficiency disease in the world affecting almost 2 billion people. In addition, anaemia due to chronic disease (ACD) is the most common cause of anaemia in hospitalized patients. Treatment for these relies on oral delivery of iron supplements. While in the long term this improves iron status, these supplements are relatively toxic to and commonly cause GI bleeding. Conversely, approximately 1:200 people of Northern European descent possess a gene mutation that predisposes them to iron overload. The main treatment for these people involves removal of blood. Although these treatments are effective an approach of choice would be the one that controls the intestinal iron absorption and macrophage efflux. Hepcidin is a small hormone produced by the liver during infection, inflammation and iron overload. It is very important in preventing diseases such as iron overload states caused by lifestyle and environmental stimuli by preventing the build-up of excess iron in tissues such as the liver and the pancreas. On the other hand, when individuals are anaemic or have low blood oxygen saturation, the liver shuts down hepcidin production in order to allow iron to be used to make new blood cells which are required to carry oxygen around the body. Recently, research in our laboratory has found that antioxidants known as polyphenols that are abundant in our foods such as onions, tea and apples can influence hepcidin expression. This suggests that it may be possible to prevent iron-overload, inflammation and infection by daily intake of the appropriate foods. We now propose to undertake further research to find out the mechanism by which these polyphenols regulate hepcidin production, and how that may be linked to changes in body iron levels and resistance to inflammatory disease

Committee	Research Committee A (Animal disease, health and welfare)
Research Topics	X – not assigned to a current Research Topic
Research Priority	Ageing Research: Lifelong Health and Wellbeing
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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