Ndfip2 is a potential regulator of the iron transporter DMT1 in the liver

The regulation of divalent metal ion transporter DMT1, the primary non-heme iron importer in mammals, is critical for maintaining iron homeostasis. Previously we identified ubiquitin-dependent regulation of DMT1 involving the Nedd4 family of ubiquitin ligases and the Ndfip1 and Ndfip2 adaptors. We also established the in vivo function of Ndfip1 in the regulation of DMT1 in the duodenum of mice. Here we have studied the function of Ndfip2 using Ndfip2-deficient mice. The DMT1 protein levels in the duodenum were comparable in wild type and Ndfip2−/− mice, as was the transport activity of isolated enterocytes. A complete blood examination showed no significant differences between wild type and Ndfip2−/− mice in any of the hematological parameters measured. However, when fed a low iron diet, female Ndfip2−/− mice showed a decrease in liver iron content, although they maintained normal serum iron levels and transferrin saturation, compared to wild type female mice that showed a reduction in serum iron and transferrin saturation. Ndfip2−/− female mice also showed an increase in DMT1 expression in the liver, with no change in male mice. We suggest that Ndfip2 controls DMT1 in the liver with female mice showing a greater response to altered dietary iron than the male mice.