Cardiac Copper Deficiency Activates a Systemic Signaling Mechanism that Communicates with the Copper Acquisition and Storage Organs

Copper (Cu) is an essential cofactor for a variety of metabolic functions, and the regulation of systemic Cu metabolism is critical to human health. Dietary Cu is absorbed through the intestine, stored in the liver, and mobilized into the circulation; however, systemic Cu homeostasis is poorly understood. We generated mice with a cardiac-specific knockout of the Ctr1 Cu transporter ( Ctr1 hrt/hrt ), resulting in cardiac Cu deficiency and severe cardiomyopathy. Unexpectedly, Ctr1 hrt/hrt mice exhibited increased serum Cu levels and a concomitant decrease in hepatic Cu stores. Expression of the ATP7A Cu exporter, thought to function predominantly in intestinal Cu acquisition, was strongly increased in liver and intestine of Ctr1 hrt/hrt mice. These studies identify ATP7A as a candidate for hepatic Cu mobilization in response to peripheral tissue demand, and illuminate a systemic regulation in which the Cu status of the heart is signaled to organs that take up and store Cu. ► Loss of cardiac Ctr1 Cu transporter ( Ctr hrt/hrt ) triggers dilated cardiomyopathy ► Ctr hrt/hrt mice demonstrate increased serum Cu levels and decreased hepatic Cu 4 ► They show increased expression of the ATP7A Cu efflux pump in liver and intestine ► Induction of ATP7A by Ctr hrt/hrt serum suggests circulating signals of Cu status