Abstract
The metal transporters ZIP14 and ZnT10 play key physiological roles in maintaining manganese (Mn) homeostasis. However, in vivo regulation of these two transporters by Mn is not understood. Here, we examined how dietary Mn intake regulates ZIP14 and ZnT10 by feeding mice a low-Mn diet, a control diet, or a high-Mn diet for 6 weeks. Inductively coupled plasma mass spectrometry was used to measure Mn and iron (Fe) levels. ZIP14 and ZnT10 protein levels were measured by western blot analysis. While mice on the high-Mn diet exhibited significantly higher levels of Mn in the blood, liver, and brain, the low-Mn diet group did not display matching reductions, indicating that high Mn intake is more effective in disrupting Mn homeostasis in mice. Additionally, Fe levels were only slightly altered, suggesting independent transport mechanisms for Mn and Fe. In the high-Mn diet group, ZIP14 and ZnT10 were both upregulated in the liver, as well as in the small intestine, indicating a coordinated role for these transporters in Mn excretion. Unexpectedly, this upregulation only occurred in male mice, with the exception of hepatic ZIP14, providing new insight into mechanisms behind widely observed sex differences in Mn homeostasis.
Highlights
Manganese (Mn) is an essential nutrient found at varying levels throughout the tissues and fluids in the body, with the highest concentrations found in the brain, liver, bone, pancreas, and kidney [1,2].Mn functions as a cofactor for enzymes involved in many physiological processes, including gluconeogenesis, N-linked glycosylation, and urea formation [3]
We found that male mice on the 2000 ppm Mn diet diet exhibited a significant upregulation of both ZIP14 and ZnT10 in the small intestine compared to exhibited a significant upregulation of both ZIP14 and ZnT10 in the small intestine compared to the the control controldiet dietgroup group(Figure (Figure7A,C), 7A,C),indicating indicating that these transporters function together during Mn that these transporters function together during Mn overload conditions to remove excess
Znt10 KO mice are more severely impacted and exhibit greater Mn accumulation than females. These findings indicate that ZIP14 and ZnT10 may play a larger role in regulating Mn homeostasis in males than in females during high Mn conditions
Summary
Mn functions as a cofactor for enzymes involved in many physiological processes, including gluconeogenesis, N-linked glycosylation, and urea formation [3]. It is vital for the function of the mitochondrial antioxidant, Mn superoxide dismutase [4]. Mn homeostasis is believed to be largely maintained by hepatobiliary excretion, where absorbed Mn is taken up into the liver and conjugated to bile for excretion through the biliary duct and intestinal tract [7,8,9]. The mechanisms underlying Mn absorption remain unknown, but it is thought that regulation of whole-body Mn homeostasis occurs at least partially at the intestinal absorption level [10]
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