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NDT Advance Access originally published online on August 6, 2008
Nephrology Dialysis Transplantation 2008 23(10):3063-3064; doi:10.1093/ndt/gfn458
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© The Author [2008]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org


New insights into intestinal iron absorption*

Walter H. Hörl

Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria

Walter H. Hörl, Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Währinger Gürtel 18-20, A-1090 Vienna, Austria. Tel: +43-1-40-400-4390; Fax: +43-1-40-400-4392; E-mail: walter.hoerl{at}meduniwien.ac.at

Keywords: intestinal iron absorption



   Introduction
Top
 Introduction
(Patho-)Physiology of enteric...
 What is in it...
 Take home message
 References
 
In the May issue of Science, Du et al. described the novel and exciting finding that the transmembrane serine protease 6 (TMPRSS6) senses iron deficiency [1]. In their study, Du et al. described a mutant mouse, which is characterized by progressive loss of body hair and microcytic anaemia. The phenotype was found to result from reduced intestinal iron absorption caused by high levels of hepcidin. Iron deprivation and anaemia suppressed hepcidin mRNA levels in the livers of wild-type mice, whereas high mRNA levels persisted in the livers of anaemic mutant mice. The high hepcidin levels in the mutant mice resulted from a splice defect in the Tmprss6 gene. This suggests that TMPRSS6 physiologically downregulates hepcidin mRNA transcription and thus promotes iron uptake [1].



   (Patho-)Physiology of enteric iron uptake
Top
 Introduction
 (Patho-)Physiology of enteric...
What is in it...
 Take home message
 References
 
Physiologically, intestinal iron absorption amounts to 1–2 mg iron per day calculated from a dietary iron intake of 12–18 mg/day. Mucosal iron absorption is determined by the amount of iron in the body iron stores and the level of erythropoiesis [2]. Dietary iron consists of haem iron and non-haem iron. Meat contains large amounts of haem iron, while vegetables are a poor source of iron. Haem iron is readily taken up by a specific transporter and degraded by haem oxygenase liberating Fe2+, which enters the intracellular iron pool. In the duodenum, non-haem Fe3+ is reduced to Fe2+ by ferric reductase (DcytB) (Figure 1). Subsequently, Fe2+ is transported across the apical enterocyte membrane by DMT1, a proton-coupled divalent metal transporter. Within the intestinal cells, Fe2+ enters mainly either the storage pool (stored in intracellular ferritin) or the transport pool (transported to the basolateral membrane and exported by ferroportin). Iron incorporation into serum apotransferrin is facilitated by the oxidation of Fe2+ to Fe3+ catalyzed by hephestin [2,3]. Intestinal iron absorption increases with a decline in body iron stores, while intestinal iron absorption is inhibited by iron overload.


Figure 1
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  		Fig. 1 Regulation of intestinal iron absorption (modified according to [2]). DCytB, ferric reductase; DMT1, divalent metal transporter-1; HJV, haemojuvelin; HFE, haemochromatosis protein; TfR, transferrin receptor; TMPRSS6, transmembrane serine protease 6.

 
Iron deficiency is the most common cause of anaemia. Iron deficiency is caused by stimulated erythropoiesis, reduced dietary iron intake, inhibition of intestinal iron absorption, inhibition of iron release from macrophages and enterocytes and/or by iron losses. Several factors such as iron overload, pro-inflammatory cytokines [4,5], HFE (haemochromatosis protein) [6], transferrin receptor 2 [7], haemojuvelin [8], the transcription factor Smad4 [9] and/or bone morphogenetic protein-2, -4 and -9 [10] promote expression of Hamp, the gene encoding hepcidin (Figure 1). The liver-derived peptide hepcidin inhibits intestinal iron absorption and cellular iron release. Vice versa, iron deficiency, hypoxia and stimulation of erythropoiesis inhibit hepcidin production. Mice with constitutive over-expression of hepcidin die from severe iron-deficient anaemia [11], while mutations in the hepcidin gene result in a severe form of juvenile haemochromatosis [12].

The mechanism of how hepcidin production in the liver blocked, is thus far unknown. Recently, the serine protease TMPRSS6 was discovered to be an essential component of a pathway that detects iron deficiency. In both humans and mice, the major site of TMPRSS6 expression is the liver. TMPRSS6 likely participates in a transmembrane signalling pathway triggered by iron deficiency. This pathway may interact with suppressive element(s) in the Hamp promoter, inhibiting hepcidin transcription in response to various stimuli (Figure 1). Overexpression or dysregulation of TMPRSS6 might cause iron overload, whereas mutational inactivation of TMPRSS6 (as demonstrated in mask mice) lowers the physiological body iron content [1].



   What is in it for the practising nephrologist?
Top
 Introduction
 (Patho-)Physiology of enteric...
 What is in it...
Take home message
 References
 
Hepcidin controls the whole-body iron content. Iron deficiency, hypoxia and stimulated erythropoiesis inhibit hepcidin production and thereby allow intestinal iron absorption. TMPRSS6 is required to sense iron deficiency and does so by lowering hepcidin transcription. Conceivably, activation of TMPRSS6 might prevent cytokine-mediated anaemia in patients with chronic disease, while selective antagonism of TMPRSS6 might be used to treat systemic iron overload (haemochromatosis). Substances or drugs that activate or antagonize TMPRSS6 are, however, currently unavailable.



   Take home message
Top
 Introduction
 (Patho-)Physiology of enteric...
 What is in it...
 Take home message
References
 
Iron deficiency activates the serine protease TMPRSS6. The protease then inhibits hepcidin transcription and thereby allows intestinal iron absorption and cellular iron release.

Conflict of interest statement. None declared.



   Notes
 
* Comment on Du X, She E, Gelbart T et al. The serine protease TMPRSS6 is required to sense iron deficiency. Science 2008; 320: 1088–1092. Back



   References
Top
 Introduction
 (Patho-)Physiology of enteric...
 What is in it...
 Take home message
 References
 

  1. Du X, She E, Gelbart T, et al. The serine protease TMPRSS6 is required to sense iron deficiency. Science (2008) 320:1088–1092.[Abstract/Free Full Text]
  2. Crichton RR, Danielson BG, Geisser P. Iron Therapy with Special Emphasis on Intravenous Administration. Bremen Uni-Med Science, 2006.
  3. Deicher R, Hörl WH. New insights into the regulation of iron homeostasis. Eur J Clin Invest (2006) 36:301–309.[CrossRef][Web of Science][Medline]
  4. Nemeth E, Valore EV, Territo M, et al. Hepcidin, a putative mediator of anemia of inflammation, is a type II acute-phase protein. Blood (2003) 101:2461–2463.[Abstract/Free Full Text]
  5. Lee P, Peng H, Gelbart T, et al. Regulation of hepcidin transcription by interleukin-1 and interleukin-6. Proc Natl Acad Sci USA (2005) 102:1906–1910.[Abstract/Free Full Text]
  6. Ahmad KA, Ahmann JR, Migas MC, et al. Decreased liver hepcidin expression in the Hfe knockout mouse. Blood Cells Mol Dis (2002) 29:361–366.[CrossRef][Web of Science][Medline]
  7. Kawabata H, Fleming RE, Gui D, et al. Expression of hepcidin is down-regulated in TfR2 mutant mice manifesting a phenotype of hereditary hemochromatosis. Blood (2005) 105:376–381.
  8. Papanikolaou G, Samuels ME, Ludwig EH, et al. Mutations in HFE2 cause iron overload in chromosome 1q-linked juvenile hemochromatosis. Nat Genet (2004) 36:77–82.[CrossRef][Web of Science][Medline]
  9. Wang RH, Li C, Xu X, et al. A role of SMAD4 in iron metabolism through the positive regulation of hepcidin expression. Cell Metab (2005) 2:399–409.[CrossRef][Web of Science][Medline]
  10. Truksa J, Peng H, Lee P, et al. Bone morphogenetic proteins 2, 4, and 9 stimulate murine hepcidin 1 expression independently of Hfe, transferrin receptor 2 (Tfr2), and IL-6. Proc Natl Acad Sci USA (2006) 103:10289–10293.[Abstract/Free Full Text]
  11. Nicolas G, Chauvet C, Viatte L, et al. The gene encoding the iron regulatory peptide hepcidin is regulated by anemia, hypoxia, and inflammation. J Clin Invest (2002) 110:1037–1044.[CrossRef][Web of Science][Medline]
  12. Roetto A, Papanikolaou G, Politou M, et al. Mutant antimicrobial peptide hepcidin is associated with severe juvenile hemochromatosis. Nat Genet (2003) 33:21–22.[CrossRef][Web of Science][Medline]
Received for publication: 2. 7.08
Accepted in revised form: 16. 7.08


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This Article
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