Vujic Spasic and colleagues have specifically ablated Hfe expression in mouse enterocytes and demonstrated that intestinal Hfe is dispensable for normal iron homeostasis.
The mechanism by which functional loss of HFE leads to hereditary hemochromatosis (HH) remains enigmatic.1 HFE is expressed in multiple cell types and tissues, leading to uncertainty as to its site of action in regulating iron homeostasis. Because loss of HFE leads to excess dietary iron absorption, initial attention focused on its potential role in the intestinal epithelium. Several observations suggested a role for HFE in duodenal crypt cells, where HFE was found to colocalize with and physically associate with transferrin receptor. Moreover, duodenal uptake of circulating transferrin-bound iron was found to be decreased in Hfe knock-out mice. The attenuated uptake of circulating iron by duodenal crypt cells lacking HFE was proposed to account for the up-regulation of genes involved in dietary iron absorption in daughter enterocytes. It was thus hypothesized that crypt cell HFE participates with transferrin receptor in sensing circulating iron and thereby modulating dietary iron absorptive capacity.2
However, the role of the liver in regulating dietary iron absorption subsequently gained currency with the discovery of the hepatocellular iron-regulatory hormone hepcidin.3 Hepcidin acts by functionally decreasing the basolateral enterocyte iron exporter ferroportin, thereby decreasing dietary iron absorption. In HFE-associated HH liver, hepcidin expression is inappropriately low, causing dietary iron absorption to be excessive. These observations argue for a more important role for HFE in the liver rather than the intestinal crypt cells.
In this issue of Blood, Vujic Spasic and colleagues elegantly tested the duodenal crypt cell hypothesis by using Cre/LoxP technology to specifically ablate Hfe expression in mouse enterocytes. Rather than demonstrating an HH phenotype, mice with deletion of Hfe in crypt and villus enterocytes were found to maintain physiological iron metabolism, as assessed by unsaturated iron-binding capacity, hepatic iron levels, and hepcidin mRNA expression. Furthermore, the expression of genes encoding the major intestinal iron transporters was unchanged in the duodenum of enterocyte-targeted Hfe knock-out mice. Thus, the authors conclude that intestinal Hfe is dispensable for the physiological control of systemic iron homeostasis.
Do these observations indicate that duodenal HFE has no role in iron metabolism? Before reaching such a conclusion, evidence showing a direct effect of HFE on cellular iron metabolism must be considered. Cell-culture studies clearly demonstrate that transfected HFE influences cellular iron status in multiple cell lines—independent of hepcidin. In the human intestinal epithelial cell line HT29 (a model for absorptive enterocytes), HFE was found to significantly decrease iron efflux and increase intracellular ferritin.4 This raises the possibility that the depletion of iron observed in HH enterocytes is due at least in part to loss of enterocyte HFE. While knock-out of Hfe in the enterocytes had no demonstrable effect on iron metabolism in the studies by Vujic Spasic et al, it is possible that the role of enterocyte Hfe becomes evident only under provocation (eg, dietary iron deficiency, increased erythropoietic iron requirement). Nonetheless, the studies by Vujic Spasic et al clearly demonstrate that Hfe plays its essential role in maintaining normal iron homeostasis in a cell type outside of the intestine.
Within the liver, HFE is expressed in hepatocytes and in Kupffer cells. It is attractive to ascribe the role for HFE in iron metabolism to hepatocytes, as this cell type expresses other genes (hepcidin, transferrin receptor 2, hemojuvelin) that lead to hemochromatosis if mutated. However, marrow transplant studies suggest that Kupffer-cell Hfe influences liver hepcidin expression.5 Perhaps HFE functions in Kupffer cells to modulate production of a paracrine factor that influences hepatocellular hepcidin expression. Indeed bone morphogenetic proteins have been shown to regulate hepatocellular hepcidin expression.6 Now that the crypt cell hypothesis has been effectively knocked out of contention, it will be informative to see the effect of targeted disruption of Hfe in specific hepatocellular populations.
Conflict-of-interest disclosure: The author declares no competing financial interests. ▪