The Function of Intestinal ZIP8 in Manganese Metabolism

Abstract

Manganese is an essential trace element required for various biological processes. An imbalance of body manganese content can have detrimental effects on human health. This study investigated the role of intestinal ZIP8 in regulating systemic manganese homeostasis and the potential for targeting ZIP8 to manage manganese-overload disorders. Using the human intestinal cell line Caco-2 cells as a model for enterocytes, we identified the localization of ZIP8 on the apical side of the enterocyte membrane. Manganese uptake experiments carried out in wild-type and ZIP8 knockout Caco-2 cells indicated that the absence of ZIP8 reduced cellular manganese accumulation. These results suggest that ZIP8 is present in enterocytes responsible for the apical manganese absorption in the intestine. We then investigated ZIP8 expression across different regions of the mouse intestine, finding it highly expressed in sections of the large intestine. To examine the physiological role of intestinal ZIP8, we generated intestine-specific Zip8 knockout mice (Zip8-ISKO) to further explore ZIP8's function in vivo. These mice showed significantly decreased manganese levels in their livers and bones that are two major organs for manganese storage, pointing to the critical role of intestinal ZIP8 in regulating systemic manganese homeostasis. We further generated double knockout (DKO) mice by crossing Zip8-ISKO mice with Zip14 knockout mice (Zip14-/-), a known mouse model for manganese overload, to examine the effects of intestinal Zip8 knockout in a high manganese environment. The DKO mice exhibited reduced manganese levels in the brain and blood when compared with Zip14-/- mice, suggesting that decreasing ZIP8 in the intestine can reduce the body's manganese burden under manganese-overload conditions. In conclusion, the present study has identified a novel role for intestinal ZIP8 in maintaining systemic manganese homeostasis. Our results have advanced the understanding of ZIP8's function and its role in manganese metabolism. Moreover, our findings may inform future strategies for managing manganese-related disorders, such as reducing manganese intake to decrease manganese accumulation in patients with manganese overload.