Dr Paul Sharp
Diabetes & Nutritional Sciences Division
School of Medicine
King's College London
3.70 Franklin-Wilkins Building
150 Stamford Street
London SE1 9NH
Tel: +44 (0)20 7848 4481
Fax: +44 (0)20 7848 4171
Senior Lecturer in Nutritional Sciences, King’s College London, 2004 - present
Lecturer/Senior Lecturer in Nutrition, University of Surrey, 2000 - 2004
Lecturer in Cell Biology & Physiology, University of East Anglia, 1995 - 2000
Regulation of body iron metabolism:
Iron is an essential trace metal in the human diet playing a crucial role in a number of physiological and biochemical functions. Iron homeostasis is maintained by matching dietary absorption to the body’s iron requirements (for haemoglobin synthesis, cellular metabolism etc). However, diseases associated with imbalances in body iron status are relatively common – for example, up to 2 billion people worldwide suffer from iron deficiency anaemia while 1:10 people of northern European decent carry a defect in the hfe gene that predisposes them to the iron loading disease haemochromatosis. Clearly therefore body iron status needs to be carefully controlled to maintain optimum human health.
The main focus of my work concerns the regulation of intestinal iron absorption. The transfer of non-haem iron across the intestinal epithelium is governed by two transporters, DMT1, which is localised to the apical membrane of enterocytes and mediates iron uptake from the gut lumen, and ferroportin, which is expressed on the basolateral surface of the cell and permits efflux into the circulation. We have shown that both the expression and cellular localisation of these transporters is regulated by the prevailing iron concentration in the diet. Using Caco-2 cells as a model intestinal epithelium we have shown that DMT1 is rapidly trafficked away from the apical membrane of these cells and targeted towards a late endosomal / lysosomal compartment following exposure to a bolus of non-haem iron. Interestingly, these events are fully reversible following the removal of the iron stimulus. We believe that this is a physiologically important mechanism that allows dietary iron absorption to be matched to the body’s requirements.
In addition to dietary iron levels, the regulation of intestinal iron absorption relies on signals generated by the main sites of iron storage (the liver) and utilisation (the bone marrow). Hepcidin, a 25 amino acid peptide hormone, is differentially expressed in the liver in response to a number of stimuli (including changes in hepatic iron content, erythropoietic drive and inflammation) and it has therefore been proposed to function as the master regulator of iron metabolism. To investigate the role of hepcidin in regulating iron metabolism, we have incubated Caco-2 intestinal epithelial cells, HuH7 hepatoma cells and THP-1 macrophages with synthetic human hepcidin and measured the expression levels of the iron transporters DMT1 and ferroportin. Our data suggest that while hepcidin decreases ferroportin expression in macrophages, its main target in intestinal cells is the DMT1-mediated iron uptake pathway. This indicates that hepcidin can interact directly with intestinal epithelia, but supports the possibility that the actions of this regulatory hormone may be tissue specific.
Vlachodimitropoulou E, Naftalin RJ, Sharp PA. Quercetin is a substrate for the transmembrane oxidoreductase Dcytb. Free Radic Biol Med. 2010 Feb 22. [Epub ahead of print] PubMed PMID: 20184953.
Thompson B, Sharp P, Elliott R, Al-Mutairi S, Fairweather-Tait SJ. Development of a Modified Caco-2 Cell Model System for Studying Iron Availability in Eggs. J Agric Food Chem. 2010 Feb 19. [Epub ahead of print] PubMed PMID:20170171.
Pavle Matak, Timothy B. Chaston, Bomee Chung, Surjit Kaila Srai, Andrew T. McKie, Paul A. Sharp. Activated macrophages induce hepcidin expression in HuH7 hepatoma cells.Haematologica. 94 (6): 773-780 (2009)
Chung B, Chaston T, Marks J, Srai SK, Sharp PA. Hepcidin decreases iron transporter expression in vivo in mouse duodenum and spleen and in vitro in THP-1 macrophages and intestinal Caco-2 cells. J Nutr. 2009 Aug;139(8):1457-62. Epub 2009 Jun 23. PubMed PMID: 19549758.
Dong C, Vincent K, Sharp P. Simultaneous mutation detection of three homoeologous genes in wheat by High Resolution Melting analysis and Mutation Surveyor. BMC Plant Biol. 2009 Dec 4;9:143. PubMed PMID: 19958559; PubMed Central PMCID: PMC2794869.