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The orchestration of body iron intake: how and where do enterocytes receive their cues?

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Abstract

Our understanding of how iron transverses the intestinal epithelium has improved greatly in recent years, although the mechanism by which body iron demands regulate this process remains poorly understood. By critically examining the earlier literature in this field and considering it in combination with recent advances we have formulated a model explaining how iron absorption could be regulated by body iron requirements. In particular, this analysis suggests that signals to alter absorption exert a direct effect on mature enterocytes rather than influencing the intestinal crypt cells. We propose that the liver plays a central role in the maintenance of iron homeostasis by regulating the expression of hepcidin in response to changes in the ratio of diferric transferrin in the circulation to the level of transferrin receptor 1. Such changes are detected by transferrin receptor 2 and the HFE/transferrin receptor 1 complex. Circulating hepcidin then directly influences the expression of Ireg1 in the mature villus enterocytes of the duodenum, thereby regulating iron absorption in response to body iron requirements. In this manner, the body can rapidly and appropriately respond to changes in iron demands by adjusting the release of iron from the duodenal enterocytes and, possibly, the macrophages of the reticuloendothelial system. This model can explain the regulation of iron absorption under normal conditions and also the inappropriate absorption seen in pathological states such as hemochromatosis and thalassemia.

Introduction

Appropriately regulated intestinal iron absorption is crucial for the maintenance of body iron homeostasis [1], yet how the intestine responds to alterations in body iron requirements is poorly understood. The discovery of several of the molecules directly involved in the uptake of iron from the lumen of the gut and its subsequent transfer to the body has resolved some of the mysteries of how iron transverses the epithelium, and descriptions of these have been the subject of several excellent reviews [2], [3], [4]. Nevertheless, previous studies have not led to the formulation of a comprehensive hypothesis able to explain body iron homeostasis under both normal and pathological conditions. In this review we make a critical appraisal of some of the earlier physiological studies on which our current understanding of intestinal iron transport is based and integrate this with newer data on the molecular basis of iron transit across the duodenal epithelium. Following this evaluation, we propose a model to explain how intestinal iron transport responds to alterations in body iron demand and how disruption of this system can lead to human disease.

Section snippets

Iron transport across the intestinal epithelium

Early studies on body iron balance revealed that humans do not appear to possess a regulated excretory mechanism for iron, so absorption in the duodenum ultimately determines the level of iron within the body [1]. The mechanistic basis of this important process was inferred from a large body of physiological work, but only in recent years have a number of the molecules responsible for iron transport by the enterocytes been identified (Fig. 1). Dietary iron in the lumen of the gut is

Regulation of iron absorption at the enterocyte level

The amount of iron transported across the small intestinal epithelium is tightly regulated to reflect the body’s iron requirements, and changes in iron absorption ultimately reflect changes in the expression of the transport molecules themselves. DMT1, Dcytb and Ireg1 are all significantly regulated by body iron status, their levels being increased under iron deficient conditions and decreased when iron supply is adequate [5], [7], [10]. Thus one or more of these molecules could potentially be

The timing of iron absorption and the role played by the intestinal crypts

The model proposed above provides a feasible mechanism for how iron absorption is controlled at the enterocyte level, but does not address the vital question of how the body informs the intestine of its iron requirements. It has been known for many years that most stimuli to alter iron absorption take several days to exert their effect [20], [21], [22], [23]. This lag period approximately coincides with the time taken for the immature crypt cells of the duodenum to mature and migrate to the

Body signals to modulate iron absorption and molecular evidence for direct effects on mature enterocytes

The nature of the body signal to modulate iron absorption is not definitively known, although a number of candidates have been entertained in the past (including ferritin and erythropoietin concentrations in the plasma) [26], [27]. However, recent evidence suggests that the anti-microbial peptide hepcidin may fulfill such a role. This peptide is synthesized by the liver and its expression is increased when body iron stores are elevated [16]. The link between hepcidin and iron homeostasis came

The regulation of hepatic hepcidin expression—a role for transferrin saturation

The current literature suggests that hepcidin signals the iron requirements of the body to the intestine, and its predominantly hepatic expression and apparent regulation by liver iron concentration has prompted suggestions that hepcidin is the mediator of the stores regulator of iron absorption [15], [32]. However, several studies have now shown that hepcidin expression can be altered without obvious changes in liver iron content [29], [31]. We have also demonstrated a positive correlation

Other disturbances in iron homeostasis

Several pathological conditions and mouse models of altered iron homeostasis should also be examined in the context of the above model.

Ineffective erythropoiesis results when the supply of iron to the erythroid marrow is inadequate [51], [64], [65]. In an iron deficient individual, marrow iron supply becomes limiting at a Tf saturation of approximately 16% [62]; however, ineffective erythropoiesis can occur at higher Tf saturations in certain pathological states such as thalassemia [66], [67],

Conclusion

McCance and Widdowson in their classic 1937 paper on iron balance concluded that “… it is quite impossible to evolve a theory to cover the absorption and excretion of iron which does not conflict with some of the published findings” [1]. While this statement is as valid today as it was 66 years ago, recent advances in the molecular analysis of iron homeostasis have greatly expanded our capacity to understand iron absorption and its regulation and have helped to resolve a number of apparent

Acknowledgements

This work was supported in part by grants from the National Health and Medical Research, Council of Australia, from the National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK-57800-1), and from the Human Frontier Science Program (Grant RGY0328/2001-M).

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