Cardiac copper deficiency activates a systemic signaling mechanism that communicates with the copper acquisition and storage organs

摘要

Copper (Cu) is an essential cofactor for a variety of metabolic functions and the regulation of systemic Cu metabolism is critical to human health. While dietary Cu is absorbed through the intestine, stored in the liver and mobilized into the circulation, systemic Cu homeostasis is poorly understood. We generated mice with a cardiac specific knock out of the Ctr1 Cu transporter, resulting in cardiac Cu deficiency (Ctr1^hrt/hrt) and severe cardiomyopathy. Unexpectedly, Ctr1^hrt/hrt mice exhibited an increase in 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 systemic regulation that signals the Cu status of the heart to Cu uptake and storage organs.