copper metabolism

The proximal small intestine is recognized as the main site of dietary copper absorption in mammals. Transport from the intestinal lumen into intestinal mucosa is a carrier-mediated process involving a saturable transport component. The overall intestinal copper uptake is influenced by amino acids, ascorbic acid, and other dietary factors.

Once in mucosal cells, approximately 80% of the newly absorbed copper is in the cytosol, mainly bound to metallothioneins (MTs). These are low-molecular weight inducible proteins with many functions including homeostasis, storage, transport and detoxification of metals. Metallothioneins bind to many metals, but in normal circumstances only Zn, Cu and Cd binding is significant.

After passage through the enterocytes, copper enters the portal circulation where it is bound to carrier proteins (primarily albumin), peptides and amino acids and is transported to the liver, with lesser amounts entering the kidney.

Copper transport in hepatocytes can be divided into three discernible but interrelated steps:
 copper uptake
 intracellular copper distribution and utilization
 copper export.

At the hepatocellular cellular level copper uptake is likely mediated by hCtr1 (SLC31A1), a copper transporter. Uptake of copper is competitively inhibited by divalent metal ions such as cadmium, manganese, zinc, and cobalt.

Once within the hepatocyte, cytoplasmic copper chaperones (COX17, HAH1/ATOX1, CCS) distribute the metal to specific cellular compartments for its incorporation into copper-requiring proteins.

HAH1/ATOX1 may function to bind copper and supply it to the Wilson disease protein (ATP7B) in the trans-Golgi network. The ATP7B gene encodes the Wilson’s disease p-type ATPase. The ATP7B protein is required for incorporation of copper into ceruloplasmin in the liver and for biliary excretion of copper. ATP7B may also be involved in the transport of copper to a vesicular compartment. Copper from these vesicles may be delivered to lysosomes.

Within hepatocytes, free copper would likely be toxic to cells. However, it appears that copper is complexed by reduced glutathione (GSH) soon after the metal enters the cell.

The importance of GSH in metal detoxification is supported by its role in the removal of toxic oxygen species. Following entry to the hepatocyte, in addition to GSH copper interacts with MT, and ceruloplasmin.

The copper chaperone for MTs has not been identified.

Copper is secreted into plasma as a complex with ceruloplasmin. This complex accounts for 90% to 95% of plasma copper.

In most mammals, copper is excreted easily, and the main route of excretion of copper is the bile. Urinary copper excretion is minimal under normal conditions since most of the copper in circulating blood is bound to ceruloplasmin or confined within the erythrocytes and very little copper crosses the glomerular capillaries.

The process of hepatobiliary copper secretion is still poorly understood. Two independent pathways have been identified for the elimination of copper from hepatocytes into bile.

The first appears to be a vesicular pathway that involves the delivery of lysosomal contents, including copper into bile. Reduction of copper excretion by microtubular disruption from colchicine administration supports the notion of a vesicular pathway.

A second pathway may involve canalicular membrane transport of copper-glutathione, and it functions when copper loads beyond physiological levels are presented to liver cells.

Copper transport into bile correlates well with the biliary excretion of glutathione, and the canalicular multispecific organic anion transporter (cMOAT) may contribute to biliary copper excretion, but the mechanism of normal biliary copper excretion is poorly understood.

Pathology: Copper metabolism anomalies

Disruption of the normal copper homeostasis or accumulation of copper in excess of metabolic requirements can lead to copper toxicity.

Copper toxicosis can be classified as primary when it results from an inherited metabolic defect, and as secondary when it is the consequence of an abnormally high intake, increased absorption, or reduced excretion of copper due to underlying pathologic processes.

 Wilson disease
 Menkes disease

References

 Fuentealba IC, Aburto EM. Animal models of copper-associated liver disease. Comp Hepatol. 2003 Apr 3;2(1):5. PMID: 12769823

 Ligoxygakis P. Copper transport meets development. Trends Genet. 2001 Aug;17(8):442. PMID: 11485812

 Mercer JF. The molecular basis of copper-transport diseases. Trends Mol Med. 2001 Feb;7(2):64-9. PMID: 11286757

 Cox DW. Genes of the copper pathway. Am J Hum Genet. 1995 Apr;56(4):828-34. PMID: 7717393