Iron Metabolism

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Lab Head: Associate Professor Greg Anderson

Iron is an essential trace element and disturbances of iron metabolism are implicated in a number of significant human diseases. The major focus of the Iron Metabolism Laboratory is to elucidate the mechanisms of cellular iron transport and the way in which these processes are regulated. A particular goal is to describe the pathways of intestinal iron absorption and to understand how absorption is altered in disorders of iron metabolism, such as the common iron overload disease haemochromatosis. To achieve this goal, we are integrating genetic and molecular studies with biochemical and physiological approaches. Recent important achievements have been the mapping and cloning of the hephaestin gene, a ceruloplasmin homologue required for transporting iron out of the intestinal epithelium and into the body, and investigating the biology of the liver-derived peptide hepcidin which acts as a systemic repressor of iron absorption.

Our current research activities include:

• A detailed investigation of the biology of iron export from intestinal epithelial cells, in order to define the role played by hephaestin and associated proteins such as the basolateral iron transporter ferroportin1
• Studies on the systemic regulation of intestinal iron transport with an emphasis on the role played by the hepatic peptide hepcidin
• Investigation of the mechanism of intestinal haem iron absorption
• The analysis of iron nutrition and the liabilities of iron supplementation in the perinatal period, with an emphasis on the regulation of iron absorption in neonates and during pregnancy.
• Utilization of our extensive haemochromatosis patient database to investigate the penetrance of the disease and its relevance to population screening for mutations in the HFE gene
• An examination of the mechanisms underlying iron overload in chronic liver disease, particularly that associated with obesity and excessive alcoholic consumption.

Mechanisms of intestinal iron absorption
Our laboratory has had a long-term interest in the mechanism by which iron from the diet traverses the intestinal epithelium. As part of this research we previously cloned a novel membrane bound ceruloplasmin homologue, named hephaestin, that is required for the movement of iron out of the intestinal enterocytes and into the circulation. This is known as the basolateral transfer step of iron absorption. We are continuing investigations into the biology of this process to elucidate the roles of hephaestin and its functional partner, the basolateral membrane iron transport protein ferroportin 1. Our studies have indicated that basolateral transfer is rate limiting for iron absorption and thus represents a key regulatory step in body iron accumulation. Assessing the relationship between basolateral transfer and iron uptake from the intestinal lumen across the enterocye brush border membrane has also formed part of this work. While these studies have concentrated on the absorption of inorganic iron, much of the iron in our diet is sequestered within haem and haem iron is very efficiently absorbed. In collaborative studies we have identified a putative haem transport protein on the enterocyte brush border membrane that has been designated HCP1. We are currently carrying out detailed analyses of the function, regulation and cellular biology of HCP1. Once within the enterocyte, haem must be broken down to release its iron and this appears to be accomplished by haem oxygenase 1. Consequently, an analysis of the function of haem oxygenase 1 in the small intestine is also a part of our ongoing investigations. This work is being carried out in collaboration with Professor Christopher Vulpe of the University of California, Berkeley and Professor Andrew McKie at King's College, London.

Regulation of iron absorption
The mechanism by which the intestine responds to alterations in body iron requirements is poorly understood, but recent evidence has strongly implicated the liver-derived peptide hepcidin in this process. Using a variety of experimental systems, we are investigating how intestinal iron transport responds to variations in body iron demand, such as those associated with changes in body iron stores and the rate of erythropoiesis, and how these changes correlate with variations in hepcidin expression. We are also studying physiological and pathological situations in which iron absorption is altered, such as during pregnancy, in the neonate, in haemochromatosis, end stage liver disease and thalassaemia, and during the acute phase response. Emphasis is being placed on analysing the expression of recently identified proteins of iron metabolism. These include hephaestin, the haemochromatosis gene product HFE, hepcidin, the iron transporters DMT1 and ferroportin 1, the ferric reductase Dcytb, hemojuvelin (mutated in most cases of juvenile haemochromatosis) and TfR2. The role of HFE in controlling iron absorption remains particularly enigmatic, but we have recently shown that hepcidin expression is inappropriately low in haemochromatosis patients and HFE knockout mice. These studies represent a major advance in our understanding of the pathogenesis of this disease. They suggest that HFE is an upstream regulator of hepcidin and imply that the major site of HFE action is in the liver and not in the small intestine as previously believed. Elucidating the signal transduction pathways linking HFE to hepcidin is an area of active investingation by our lab. Studies by our group and others have also shown that HFE is able to interact with a transferrin receptor/transferrin complex, indicating a link between HFE and cellular iron uptake. We have recently proposed that the degree of saturation of plasma transferrin with iron could be an important signal in influencing hepcidin expression through the HFE pathway. Our HFE studies are continuing in collaboration with the laboratories of Dr Nathan Subramaniam and Dr Grant Ramm at QIMR.

Population and clinical studies of haemochromatosis and iron metabolism in liver disease
Our laboratory has had a long term interest in the clinical aspects and population prevalence of the common iron overload disease haemochromatosis and we have accumulated a very large database of haemochromatosis families. Studies in this area are being carried out under the guidance of Professor Lawrie Powell. Haemochromatosis results from mutations in the HFE gene and, in Australia, almost all disease is due to a single mutation (C282Y). Current projects include (1) An investigation of the rate of iron accumulation in haemochromatosis patients, particularly those who are apparently not expressing the disease when initially genotyped; (2) Analysis of the clinical expression of the disease in C282Y/H63D compound heterozygotes; (3) The identification of genetic modifiers of the iron loading phenotype in haemochromatosis; (4) Evaluating the effects of environmental factors on disease phenotype; and (5) Investigating the molecular basis of iron overload in patients without HFE mutations. These studies are being carried out in collaboration with Associate Professor Katie Allen at the Murdoch Institute, Melbourne, Dr Lyle Gurrin and members of the HealthIron Study at the University of Melbourne, Professor John Olynyk at the University of Western Australia and Drs Grant Ramm and Nathan Subramaniam at QIMR. In addition to our haemochromatosis studies, we have initiated investigations into the role played by iron in the pathogenesis of other liver diseases. Of particular interest are alcoholic liver disease and fatty liver disease, both major public health problems in Australia. In the former, hepatic hepcidin levels decline, whereas in the latter, they increase. We are currently investigating the molecular mechanisms that lead to altered hepcidin expression in these conditions. These studies are being carried out in collaboration with Professor Darrell Crawford at Greenslopes Hospital and Drs Linda Fletcher, Kim Bridle and Graeme MacDonald at the Princess Alexandra Hospital in Brisbane.

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Staff

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Collaborators

• Dr Andrew McKie, King's College, London, UK
• Dr Gordon Mclaren, University of California, Irvine, USA
• Dr Chris Tselepis, University of Birmingham, Birmingham, UK
• Professor Chris Vulpe, University of California, Berkeley, USA

• Professor Paul Alewood, University of Queensland
• Dr Katie Allen, Murdoch Institute, Melbourne
• Associate Professor Graham Baldwin and Professor Arthur Shulkes, University of Melbourne
• Dr Linda Fletcher, Dr Mandy Heritage and Dr Graeme McDonald, Princess Alexandra Hospital
• Professor Darrell Crawford, Greenslopes Hospital
• Dr Lyle Gurrin, University of Melbourne
• Dr John Olynyk and Dr Debbie Trinder, University of Western Australia
• Dr Grant Ramm, QIMR
• Dr David Reid, University of Tasmania
• Dr Nathan Subramaniam, QIMR

Key Publications

Allen KJ, Gurrin LC, Constantine CC, Osborne NJ, Delatycki MB, Nicoll AJ, McLaren CE, Bahlo M, Fletcher AS, Nisselle AE, Forrest S, Vulpe CD, Anderson GJ, Southey MC, Giles GG, English DR, Hopper JL, Olynyk JK, Powell LW and Gertig DM. 2008. Iron-overload-related disease in HFE hereditary hemochromatosis. N Engl J Med. 358: 221-230.

Frazer DM, Wilkins SJ and Anderson GJ. 2007. Elevated iron absorption in the neonatal rat reflects high expression of iron transport genes in the distal alimentary tract. Am J Physiol. 293: G525-531.

Walsh A, Dixon JL, Ramm GA, Hewett DG, Lincoln D, Anderson GJ, Subramaniam VN, Dodemaide J, Cavanaugh JA, Bassett ML and Powell LW. 2006. The clinical relevance of compound heterozygosity for the C282Y and H63D substitutions in hemochromatosis. Clin Gastroenterol Hepatol. 4: 1403-1410.

Smyth DJ, Glanfield A, McManus DP, Hacker E, Blair S, Anderson GJ and Jones MK. 2006. Two isoforms of a divalent metal transporter (DMT1) in Schistosoma mansoni suggest a surface-associated pathway for iron absorption in schistosomes. J Biol Chem. 281: 2242-2248.

Wilkins SJ, Frazer DM, Millard KN, McLaren GD and Anderson GJ. 2006. Iron metabolism in the hemoglobin deficit mouse: Correlation of diferric transferrin with hepcidin expression. Blood. 107: 1659-1664.

Powell LW, Dixon JL, Ramm GA, Purdie DM, Lincoln DJ, Anderson GJ, Subramaniam VN, Hewett DG, Searle JW, Fletcher LM, Crawford DH, Rodgers H, Allen KJ, Cavanaugh JA and Bassett ML. 2006. Screening for hemochromatosis in asymptomatic subjects with or without a family history. Archives Int Med 166: 294-301.

Shayeghi M, Latunde-dada GO, Oakhill JS, Takeuchi K, Laftah A, Halliday N, Khan Y, Warley A, McCann FE, Hider RC, Frazer DM, Anderson GJ, Vulpe CD, Simpson RJ and McKie AT. 2005. Identification of an intestinal heme transporter. Cell. 122: 789-801.

Frazer DM, Wilkins SJ, Millard KN, McKie AT, Vulpe CD and Anderson GJ. 2004. Increased hepcidin expression and hypoferraemia associated with an acute phase response are not affected by inactivation of HFE. Br J Haematol. 126: 434-436.

Frazer DM, Inglis HR, Wilkins SJ, Millard KN, Steele TM, McLaren GD, McKie AT, Vulpe CD and Anderson GJ. 2004. Delayed hepcidin response explains the lag period in iron absorption following a stimulus to increase erythropoiesis. Gut. 53: 1509-1515.

Chen H, Attieh ZK, Su T, Syed BA, Gao H, Alaeddine RM, Fox TC, Usta J, Naylor CE, Evans RW, McKie AT, Anderson GJ and Vulpe CD. 2004. Hephaestin is a ferroxidase that maintains partial activity in the sex-linked anemia mouse. Blood. 103: 3933-3939.

Millard KN, Frazer DM, Wilkins SJ and Anderson GJ. 2004. Changes in the expression of intestinal iron transport and hepatic regulatory molecules explain the enhanced iron absorption associated with pregnancy in the rat. Gut. 53:655-660.

Stuart KA, Anderson GJ, Frazer DM, Murphy TL, Powell LW, Fletcher LM and Crawford DH. 2004. Increased duodenal expression of DMT1 and Ireg1 in cirrhosis. Hepatology.39: 492-499.

Kuo Y-M, Su T, Chen H, Attieh Z, Anderson GJ, Gitschier J and Vulpe CD. 2004. Mislocalization of hephaestin, a predicted multi-copper ferroxidase involved in basolateral intestinal iron transport, in the sex-linked anaemia mouse. Gut. 53: 201-206.

Chen H, Su T, Attieh ZK, Fox TC, McKie AT, ANDERSON GJ and Vulpe CD. 2003. Systemic regulation of hephaestin and Ireg1 revealed in studies of genetic and nutritional iron deficiency. Blood. 102: 1893-1899.

Frazer DM and Anderson GJ. 2003. Orchestrating body iron intake: How and where do intestinal cells take their cues? Blood Cells Molec Dis. 30: 288-297.

Bridle KR, Frazer DM, Wilkins SJ, Dixon JL, Crawford DHG, Subramaniam VN, Powell LW, Anderson GJ and Ramm GA. 2003. Disrupted hepcidin regulation in HFE-associated haemochromatosis and the liver as a regulator of body iron homeostasis. Lancet. 361: 669-673.

Stuart KA, Anderson GJ, Frazer DM, Powell LW, McCullen M, Fletcher LM and Crawford DHG. 2003. Duodenal expression of iron transport molecules in untreated hemochromatosis subjects. Gut. 52: 953-959.

Frazer DM, Wilkins SJ, Becker EM, Murphy TL, Vulpe CD, McKie AT and Anderson GJ. 2003. A rapid decrease in the expression of DMT1 and Dcytb but not Ireg1 or hephaestin explains the mucosal block phenomenon of iron absorption. Gut. 52: 340-346.

Frazer DM, Wilkins SJ, Becker EM, Vulpe CD, McKie AT, Trinder D, Cleghorn GJ and Anderson GJ. 2002. Hepcidin expression inversely correlates with the expression of duodenal iron transporters and iron absorption in rats. Gastroenterology. 123: 835-844.

Frazer DM, Vulpe CD, McKie AT, Cleghorn GJ and Anderson GJ. 2001. Cloning and gastrointestinal expression of the rat hephaestin gene: relationship to other proteins of iron transport. American Journal of Physiology 281:G931-G939.

Vulpe CD, Kuo Y-M, Libina N, Gitschier J, Askwith C, Murphy TL, Cowley L, and Anderson GJ. 1999. Hephaestin: a ceruloplasmin homologue implicated in intestinal iron uptake and its defect in the sla mouse. Nature Genetics. 21:195-199.

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