Copper is a trace element that is essential for many biological processes in the body. Because excess copper is toxic, copper metabolism is tightly regulated. Copper from the diet and water is mainly absorbed in the small intestine via copper transporter 1 (CTR1) at the apical membrane of the enterocytes. At the basolateral side of the enterocytes the copper transporting ATPase alpha (ATP7A) shuttles copper to the portal circulation for delivery to the liver. The liver is the central organ in coppermetabolism and functions in copper storage, excretion and redistribution of copper to other organs. After uptake in the hepatocyte through CTR1, copper is immediately bound by proteins to prevent oxidative damage caused by hydroxyl radicals created by free copper. The copper chaperones COX17, CCS, and ATOX1 shuttle copper to their destination molecules CCO, SOD1, and ATP7A/ATP7B respectively. In the hepatocyte, both copper transporting ATPases reside in the trans-Golgi network (TGN). ATP7B has an important role in the incorporation of copper atoms on ceruloplasmin, which is an important copper transport protein in the blood and plays a role in iron metabolism. When copper levels are high, ATP7B interacts with COMMD1 to excrete copper into the bile. Inthe hepatocyte, ATP7A was identified to have an important role in mobilizing hepatic copper stores in case of peripheral copper deficiency. The importance of ATP7A and ATP7B in copper metabolism has been illustrated in humans that are diseased due to mutations in either gene. Defects in ATP7A result in copper deficiency and cause Menkes disease. Wilson disease is caused by mutations in ATP7B and is characterized by copper accumulation in liver and neural tissue.
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