Zip14 (solute carrier family 39, member of 14, SLC39A14) is a transmembrane metal-ion transporter. The mammalian ZIP (Z&barbelow;rt-, Irt-like Protein) family of transmembrane transporters consists of 14 members. Zip14 has been shown to transport iron as well as zinc into hepatocytes. The studies described here investigated the relationship between Zip14 and iron status by using animal models of dietary iron deficiency and overload. Weanling male Sprague-Dawley rats were fed modified AIN-93G purified rodent diets that contained 10 ppm iron (FeD), 50 ppm iron (FeA) or 1.9% carbonyl iron (2% FeO) for 3 wk. Zip14 expressions in three major iron-loading tissues were analyzed: the liver, pancreas and heart. Hepatic Zip14 protein levels did not differ in response to dietary iron status. In the pancreas and heart, Zip14 protein levels were significantly up-regulated by 2% carbonyl iron. The higher levels of Zip14 protein were not associated with higher levels of Zip14 mRNA, indicating that Zip14 expression is post-transcriptionally regulated by iron.

The localization of Zip14 expression was performed by immunohistochemistry with the three major important tissues in the iron metabolism: liver, pancreas, and duodenum. In the liver, Zip14 protein was highly localized in the hepatocyte membrane along with sinusoids by 2% carbonyl iron. In the pancreas, highly intense Zip14 immunostaining was localized on perinuclear regions and the plasma membrane in acinar cells. In the duodenum, the immunostaining of Zip14 was faint in FeD, but unexpectedly, 2% FeO showed strong signals of Zip14 in the basolateral membrane of the villus region.

To test whether some of the ZIP family members respond to dietary iron status in the liver, the mRNA expression of ZIP family transporters was analyzed by qRT-PCR. ZIP5 mRNA expression was highly induced in iron-loaded rat livers relative to the control livers. In addition, the levels of ZIP6, ZIP7, and ZIP10 mRNA were significantly down-regulated by dietary iron overload. However, dietary iron deficiency and overload also induced small, but significant, modulation in hepatic levels of other metals. Thus, it is possible that differences in the levels of these metals affected the ZIP expression. Collectively, these observations suggest that ZIP5, ZIP6, ZIP7, ZIP10 may play a role in hepatic iron/metal homeostasis during iron deficiency and iron overload.