School of Nutritional Sciences and Wellness, The University of Arizona, Tucson, AZ 85721, USA.
Int J Mol Sci. 2023 Mar 22;24(6):5962. doi: 10.3390/ijms24065962.
ZIP8 is a newly identified manganese transporter. A lack of functional ZIP8 results in severe manganese deficiency in both humans and mice, indicating that ZIP8 plays a crucial role in maintaining body manganese homeostasis. Despite a well-acknowledged connection between ZIP8 and manganese metabolism, how ZIP8 is regulated under high-manganese conditions remains unclear. The primary goal of this study was to examine the regulation of ZIP8 by high-manganese intake. We used both neonatal and adult mouse models in which mice were supplied with dietary sources containing either a normal or a high level of manganese. We discovered that high-manganese intake caused a reduction in liver ZIP8 protein in young mice. Since a decrease in hepatic ZIP8 leads to reduced manganese reabsorption from the bile, our study identified a novel mechanism for the regulation of manganese homeostasis under high-manganese conditions: high dietary manganese intake results in a decrease in ZIP8 in the liver, which in turn decreases the reabsorption of manganese from the bile to prevent manganese overload in the liver. Interestingly, we found that a high-manganese diet did not cause a decrease in hepatic ZIP8 in adult animals. To determine the potential reason for this age-dependent variation, we compared the expressions of liver ZIP8 in 3-week-old and 12-week-old mice. We found that liver ZIP8 protein content in 12-week-old mice decreases when compared with that of 3-week-old mice under normal conditions. Overall, results from this study provide novel insights to facilitate the understanding of ZIP8's function in regulating manganese metabolism.
ZIP8 是一种新发现的锰转运体。人类和小鼠中 ZIP8 功能缺失会导致严重的锰缺乏症，这表明 ZIP8 在维持体内锰稳态中起着至关重要的作用。尽管 ZIP8 与锰代谢之间存在明确的联系，但在高锰条件下 ZIP8 是如何被调节的仍不清楚。本研究的主要目的是研究高锰摄入对 ZIP8 的调节作用。我们使用了新生和成年小鼠模型，这些小鼠分别通过饮食摄入正常或高水平的锰。我们发现，高锰摄入会导致年轻小鼠肝脏 ZIP8 蛋白减少。由于肝脏 ZIP8 的减少导致胆汁中锰的重吸收减少，我们的研究确定了高锰条件下调节锰稳态的一种新机制：高膳食锰摄入导致肝脏 ZIP8 减少，进而减少胆汁中锰的重吸收，以防止肝脏中锰过载。有趣的是，我们发现高锰饮食不会导致成年动物肝脏中 ZIP8 的减少。为了确定这种年龄依赖性差异的潜在原因，我们比较了 3 周龄和 12 周龄小鼠肝脏 ZIP8 的表达。我们发现，在正常情况下，12 周龄小鼠肝脏 ZIP8 蛋白含量较 3 周龄小鼠减少。总的来说，这项研究的结果为理解 ZIP8 在调节锰代谢中的作用提供了新的见解。
