The intestinal metal transporter ZIP14 maintains systemic manganese homeostasis.

ZIP14 (encoded by the solute carrier 39 family member 14 (SLC39A14) gene) is a manganese transporter that is abundantly expressed in the liver and small intestine. Loss-of-function mutations in SLC39A14 cause severe hypermanganesemia. Because the liver is regarded as the main regulatory organ involved in manganese homeostasis, impaired hepatic manganese uptake for subsequent biliary excretion has been proposed as the underlying disease mechanism. However, liver-specific Zip14 KO mice exhibit decreased manganese only in the liver and do not develop manganese accumulation in other tissues under normal conditions. This suggests that impaired hepatobiliary excretion is not the primary cause for manganese overload observed in individuals lacking functional ZIP14. We therefore hypothesized that increased intestinal manganese absorption could induce manganese hyperaccumulation when ZIP14 is inactivated. To elucidate the role of ZIP14 in manganese absorption, here we used CaCo-2 Transwell cultures as a model system for intestinal epithelia. The generation of a ZIP14-deficient CaCo-2 cell line enabled the identification of ZIP14 as the major transporter mediating basolateral manganese uptake in enterocytes. Lack of ZIP14 severely impaired basolateral-to-apical (secretory) manganese transport and strongly enhanced manganese transport in the apical-to-basolateral (absorptive) direction. Mechanistic studies provided evidence that ZIP14 restricts manganese transport in the absorptive direction via direct basolateral reuptake of freshly absorbed manganese. In support of such function of intestinal ZIP14 in vivo, manganese levels in the livers and brains of intestine-specific Zip14 KO mice were significantly elevated. Our findings highlight the importance of intestinal ZIP14 in regulating systemic manganese homeostasis.