Regulation of Metal Transporters, ZIP14 and ZnT10, by Manganese Intake in Mice

Abstract

Manganese (Mn) is an essential trace mineral vital for many biological processes. ZIP14, ZnT10, and ZIP8 are proteins first identified as transporters for iron (Fe) and zinc (Zn). Current research now indicates a key role for these three metal transporters in regulating Mn homeostasis. However, there is still limited evidence to explain the regulatory mechanisms or how Mn status influences levels of Fe and Zn, which are believed to share several transport pathways with Mn. Here, we examined the effect of Mn intake on the regulation of these metal transporters by feeding mice a low-Mn diet, control diet, or high-Mn diet for 6 weeks. Levels of Mn, Fe, and Zn were measured using inductively coupled plasma mass spectrometry and protein levels of ZIP14, ZnT10, and ZIP8 were analyzed by Western Blot. While mice on the high-Mn diet exhibited significantly higher levels of Mn in the blood, liver, spleen, brain, and lungs, mice on the low-Mn diet did not display matching reductions, indicating Mn homeostasis is more challenging to maintain with high intake of Mn compared to low. Zn levels were not considerably altered and only minor reductions in Fe levels were observed in mice on the high-Mn diet, suggesting the regulation of these metals may not be as intertwined as previously believed. Interestingly, there was no difference in hepatic ZIP8 levels among the three diet groups. In response to the high-Mn diet, ZIP14 and ZnT10 were both upregulated in the liver, as well as in the small intestine, indicating a coordinated role for these two transporters in Mn excretion. Unexpectedly, this upregulation was only evident in male mice, with the exception of hepatic ZIP14, providing new insight into the mechanisms behind widely observed sex differences in Mn homeostasis.