Deletion of hepatic Ctr1 reveals its function in copper acquisition and compensatory mechanisms for copper homeostasis.
Copper is a vital trace element required for normal growth and development of many organisms. To determine the roles for copper transporter 1 (Ctr1) in hepatic copper metabolism and the contribution of the liver to systemic copper homeostasis, we have generated and characterized mice in which Ctr1 is deleted specifically in the liver. These mice express less than 10% residual Ctr1 protein in the liver and exhibit a small but significant growth retardation, which disappears with age. Hepatic copper concentrations and the activities of copper-requiring enzymes are reduced; however, mild copper deficiency relative to Ctr1 protein deficit indicates compensatory mechanisms for copper metabolism. Copper concentrations of other organs did not alter despite the defect in hepatic copper uptake. Whereas biliary copper excretion is reduced, urinary copper concentration in these mice is higher than that of control mice. Our data indicate that Ctr1 plays a critical role in copper acquisition in the liver, and, when Ctr1 expression is compromised, compensatory mechanisms facilitate copper uptake and/or retention in the liver and excretion of copper via urine.
Kim
Heejeong
H
Redox Biology Center, Department of Biochemistry, University of Nebraska, Lincoln, NE 68588-0664, USA.
Son
Hwa-Young
HY
Bailey
Sarah M
SM
Lee
Jaekwon
J
D000367:Age Factors; D000375:Aging / Q000378:metabolism; D000818:Animals; D001646:Bile / Q000378:metabolism; D027682:Cation Transport Proteins / Q000172:deficiency* / Q000235:genetics; D002570:Ceruloplasmin / Q000378:metabolism; D003300:Copper / Q000097:blood / Q000172:deficiency / Q000378:metabolism* / Q000652:urine; D000079923:Copper Transporter 1; D003576:Electron Transport Complex IV / Q000378:metabolism; D005260:Female; D006130:Growth Disorders / Q000235:genetics / Q000378:metabolism; D006706:Homeostasis; D007501:Iron / Q000378:metabolism; D008099:Liver / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D013482:Superoxide Dismutase / Q000378:metabolism; D015032:Zinc / Q000378:metabolism
D027682:Cation Transport Proteins; D000079923:Copper Transporter 1; C490077:Slc31a1 protein, mouse; D003300:Copper; D007501:Iron; D013482:Superoxide Dismutase; D002570:Ceruloplasmin; D003576:Electron Transport Complex IV; D015032:Zinc