Department of Animal and Avian Sciences, University of Maryland, College Park, MD 20742, USA.
Department of Biochemistry and Redox Biology Center, University of Nebraska, Lincoln, NE 68516, USA.
Sci Rep. 2017 Sep 20;7(1):12001. doi: 10.1038/s41598-017-11961-z.
Copper (Cu) is an essential cofactor for various enzymatic activities including mitochondrial electron transport, iron mobilization, and peptide hormone maturation. Consequently, Cu dysregulation is associated with fatal neonatal disease, liver and cardiac dysfunction, and anemia. While the Cu transporter ATP7A plays a major role in both intestinal Cu mobilization to the periphery and prevention of Cu over-accumulation, it is unclear how regulation of ATP7A contributes to Cu homeostasis in response to systemic Cu fluctuation. Here we show, using Cu-deficient mouse models, that steady-state levels of ATP7A are lower in peripheral tissues (including the heart, spleen, and liver) under Cu deficiency and that subcutaneous administration of Cu to these animals restore normal ATP7A levels in these tissues. Strikingly, ATP7A in the intestine is regulated in the opposite manner - low systemic Cu increases ATP7A while subcutaneous Cu administration decreases ATP7A suggesting that intestine-specific non-autonomous regulation of ATP7A abundance may serve as a key homeostatic control for Cu export into the circulation. Our results support a systemic model for how a single transporter can be inversely regulated in a tissue-specific manner to maintain organismal Cu homeostasis.
铜（Cu）是多种酶活性的必需辅助因子，包括线粒体电子传递、铁动员和肽激素成熟。因此，Cu 失调与致命的新生儿疾病、肝和心脏功能障碍以及贫血有关。虽然 Cu 转运体 ATP7A 在肠内向周围组织动员 Cu 和防止 Cu 过度积累方面发挥着重要作用，但尚不清楚 ATP7A 的调节如何在应对系统性 Cu 波动时有助于 Cu 体内平衡。在这里，我们使用 Cu 缺乏的小鼠模型表明，在 Cu 缺乏时，外周组织（包括心脏、脾脏和肝脏）中的 ATP7A 水平较低，而向这些动物皮下给予 Cu 可恢复这些组织中正常的 ATP7A 水平。引人注目的是，肠道中的 ATP7A 以相反的方式受到调节——低系统性 Cu 增加 ATP7A，而皮下 Cu 给药则降低 ATP7A，表明肠道特异性非自主调节 ATP7A 丰度可能是 Cu 向循环中输出的关键体内平衡控制。我们的研究结果支持了一种系统模型，即单一转运体如何以组织特异性的方式被反向调节以维持机体 Cu 体内平衡。
