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Sci Rep. 2017 Sep 20;7(1):12001. doi: 10.1038/s41598-017-11961-z.

Organ-specific regulation of ATP7A abundance is coordinated with systemic copper homeostasis.

Author information

1
Department of Animal and Avian Sciences, University of Maryland, College Park, MD 20742, USA.
2
Department of Biochemistry and Redox Biology Center, University of Nebraska, Lincoln, NE 68516, USA.
3
Department of Animal and Avian Sciences, University of Maryland, College Park, MD 20742, USA. bekim@umd.edu.
4
Biological Sciences Graduate Program, University of Maryland, College Park, MD 20742, USA. bekim@umd.edu.

Abstract

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.

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