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Is TfR2 the iron sensor?

Tomas Ganz

Comment on Johnson and Enns, page 4287, and comment on Robb and Wessling-Resnick, page 4294

The liver has a central role in regulating the absorption of iron from the diet and the release of stored iron. How does the liver monitor the iron requirements of erythropoiesis? Two articles provide evidence that hepatic transferrin receptor 2 (TfR2) molecules sense the concentration of diferric transferrin in plasma.

Plasma transferrin saturation (Fe/total iron-binding capacity [TIBC]) is measured in clinical laboratories as an indicator of iron deficiency or excess. Johnson and Enns and Robb and Wessling-Resnick present evidence that humans and animals use transferrin receptor 2 (TfR2) to “measure” the concentration of holotransferrin (iron-saturated transferrin). When these studies are extended to identify the molecules that interact with TfR2, the receptor could turn out to be the homeostatic sensor of plasma iron content for the regulation of iron absorption and its tissue distribution.

The 2 papers show that increasing concentrations of holotransferrin but not apotransferrin (iron-free transferrin) increase TfR2 protein levels in hepatocyte-derived cell lines, probably by protecting the receptor from degradation. The effect is hepatocyte specific and not seen in other cell lines that display TfR2. This is in agreement with a number of recent studies that point to the liver as the principal regulator of iron absorption and distribution.1,2 TfR2 binds holotransferrin with a dissociation constant (Kd) of about 25 nM, which should in principle preclude this receptor from having a regulatory role, since it should be fully saturated at physiologic concentrations of holotransferrin (3-6 μM). Curiously, the half-maximal effect on TfR2 stabilization occurs at about 2.5 μM, which would allow the receptor to sense throughout the physiologic range. It is possible that holotransferrin stabilizes TfR2 through binding at an additional site, which could be on TfR2 itself or on an associated molecule.

Figure1

Iron sensing and the homeostatic regulation of iron absorption, release from stores, and plasma iron content. Iron flows and signals are denoted by red arrows; the putative iron sensor complex and its signaling pathways by green symbols and arrows; and the resulting hepcidin synthesis and secretion by a blue arrow. Importantly, noniron signals, including inflammation (interleukin-6 [IL-6]), and anemia or hypoxia, also regulate hepcidin synthesis but for simplicity are not shown in this diagram.

Importantly, the regulation of TfR2 expression by holotransferrin is also seen in animal models. In mice and rats, TfR2 is increased in the liver when diet or genetics increase the concentration of holotransferrin, and TfR2 is decreased when holotransferrin is low, regardless of the concurrent presence of anemia or total iron load in the liver. The relative changes in TfR2 appear to be smaller than those seen in HepG2 cells, suggesting that regulatory factors other than holotransferrin may intervene in vivo.

Based on independent genetic evidence in humans and mice, TfR2 is an attractive candidate for the homeostatic iron sensor because it is one of a handful of genes whose homozygous disruption causes dysregulated iron absorption and distribution, resulting in primary hemochromatosis.3 The homeostatic circuit must also contain hemojuvelin (HJV) and hepcidin, since their homozygous disruption causes juvenile hemochromatosis, a particularly severe form of the disease. HFE probably plays a modulating role in this circuit because its disruption causes a milder form of hemochromatosis. Combining the genetic evidence with experimental studies in humans and animal models, it now appears that in the liver, TfR2, hemojuvelin (HJV), and HFE all act as regulators of hepcidin synthesis and secretion. Hepcidin, the iron-regulatory hormone, circulates in blood to the proximal small intestine, where it acts as a regulator of iron absorption, and to hepatocytes and macrophages, where hepcidin regulates iron storage and release (Figure 1). How hepcidin synthesis is regulated by TfR2, hemojuvelin, and HFE is not clear. The major difficulty has been the inability to reconstitute the regulatory circuit in a single cell type, as was again confirmed by Johnson and Enns. Although iron loading in mice or humans increases their hepatic hepcidin production, isolated human or mouse hepatocytes, or hepatocyte cell lines, do not increase their hepcidin synthesis when treated with holotransferrin or other forms of iron. This suggests that another cell type or its product may be required to complete the circuitry. In the last few years, the field of iron metabolism has been reinvigorated by the identification of the principal molecules involved in its regulation.2 Elucidating how these molecules function individually and how they interact with each other is likely to provide much excitement for years to come.

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