Overview Of Copper Homeostasis In Humans 21 Whole Body Copper Homeostasis

There is a large body of early literature on the physiology of copper, which is now in the process of being reinterpreted in the light of the recent molecular advances. Here, we present only a brief summary of the overall process of copper transport; for more detailed information, the early work is well summarized in a number of reviews (2-4). More recently, reviews incorporating the molecular advances have appeared (5-7).

The amount of copper in the body is regulated by the rate of absorption of dietary copper across the intestinal epithelium vs the rate of excretion of copper into bile by hepatocytes. Although some regulation of copper status is achieved by alteration of the extent of absorption of dietary copper at the small intestine, changes in the rate of biliary excretion of copper appear to be principally responsible for overall copper balance. Figure 1 shows an outline of the major routes of copper in the body and the sites at which blocks occur in Menkes disease (MD) and Wilson's disease (WD).

Most dietary copper is absorbed in the small intestine (step 1, Fig. 1) and is transported across the basolateral membrane of the enterocyte into venules that collect into the portal vein (2). This step is likely to involve the Menkes Cu-ATPase, ATP7A, because patients with Menkes disease accumulate copper within the intestinal epithelium. The regulation of absorption is discussed in more detail below (Section 2.3.). Once copper enters the blood, it either is bound to albumin (8), complexed with histi-dine (9), or attached to a macroglobulin termed transcuprein (3) and transported to the liver. The liver is a major player in copper homeostasis and rapidly removes most of the absorbed copper from the blood. About 50% of copper is taken up by the liver within 10 min of entry into the circulation (10). Copper uptake by hepatocytes (step 2, Fig. 1) is a carrier-mediated process, not dependent on metabolic energy, and can occur from the copper-histidine complex (11).

In the hepatocyte, copper is incorporated into the blue multicopper oxidase, ceruloplasmin (2). The Wilson Cu-ATPase, ATP7B, is required for the incorporation of copper into ceruloplasmin; thus, this process is blocked in Wilson's disease (step 3a, Fig. 1) and low plasma ceruloplasmin is a feature of most patients with this disorder. Ceruloplasmin is the major copper protein in plasma and may play a part in supplying copper to tissues, a role supported, but not proven, by the finding of ceruloplasmin receptors in various tissues (12). The role of ceruloplasmin in copper transport is still unclear, but the absence of any obvious disturbance of copper transport in the human disease, aceruloplasminemia, and the accumulation of iron in tissues of these patients suggest that the main role for this protein is in iron metabolism rather than copper transport (13). If the amount of copper in the liver is excessive, copper is excreted in the bile (step 3b, Fig. 1). Biliary excretion of copper is the main regulatory step in maintaining overall copper homeostasis and requires ATP7B. Copper in the bile cannot be reabsorbed and is excreted in the feces (2). The molecular basis of the regulation of biliary copper excretion is becoming clearer and is discussed in more detail later. Patients with WD have both defective biliary excretion and most do not incorporate copper into ceruloplasmin; thus, in this disease, copper accumulates in the liver to toxic levels.

Normally, very little copper is excreted in the urine, most apparently being resorbed in the kidney tubules (step 4, Fig. 1). In patients with WD, urinary copper secretion is elevated, presumably caused by copper release from the damaged liver (4). In patients with Menkes disease and the mouse models of this disorder, copper becomes trapped in the proximal tubular cells of kidney, suggesting that ATP7A is required to pump the copper from these cells back into the circulation. This causes the apparently paradoxical situation of copper accumulation in some tissues of a patient suffering the effects of profound copper deficiency, but this copper is unavailable for the organ most sensitive to copper deprivation, the brain (4,14). The copper concentration in the liver of Menkes patients is very

Fig. 1. An outline of the pathways of copper in the body and the blocks in Menkes (MD) and Wilson's disease (WD). Copper is absorbed in the small intestine (step 1) and the majority is taken up by the liver (step 2), which either incorporates the copper into ceruloplasmin (step 3 a) that is secreted into the plasma, or if there is excess copper present, it is secreted into the bile (step 3b). Both steps 3a and 3b are defective in WD, leading to an accumulation of copper in the liver. Little copper is excreted in the urine, most is resorbed in the kidney tubules. In MD, blocks to copper transport occur at the small intestine, reducing the overall uptake of copper and across of the blood-brain barrier (step 4), resulting in a very low brain copper concentrations, which lead to severe neurological abnormalities. In addition, the efflux of copper from tissues to the circulation is blocked in MD, causing a paradoxical accumulation of copper even though the patient has a profound copper deficiency.

Fig. 1. An outline of the pathways of copper in the body and the blocks in Menkes (MD) and Wilson's disease (WD). Copper is absorbed in the small intestine (step 1) and the majority is taken up by the liver (step 2), which either incorporates the copper into ceruloplasmin (step 3 a) that is secreted into the plasma, or if there is excess copper present, it is secreted into the bile (step 3b). Both steps 3a and 3b are defective in WD, leading to an accumulation of copper in the liver. Little copper is excreted in the urine, most is resorbed in the kidney tubules. In MD, blocks to copper transport occur at the small intestine, reducing the overall uptake of copper and across of the blood-brain barrier (step 4), resulting in a very low brain copper concentrations, which lead to severe neurological abnormalities. In addition, the efflux of copper from tissues to the circulation is blocked in MD, causing a paradoxical accumulation of copper even though the patient has a profound copper deficiency.

low, as ATP7B is functioning normally, providing what little copper is available for incorporation into ceruloplasmin.

The transport of copper into the brain (step 5, Fig. 1) is essential for normal brain development. To enter the brain, copper must traverse the vascular endothelial cells that comprise the blood-brain barrier. The requirement of ATP7A for this step has been directly demonstrated by the accumulation of copper in the astrocytes and vascular endothelium in the brain of mouse models of Menkes disease and ATP7A is expressed in these (15). Thus, in human patients as well as in mutant mice, blood copper is probably trapped in the blood-brain barrier and not transported to neurones. The brain of patients with Menkes disease is severely copper deficient as a result of several blockages to copper transport: one at the small intestine, a second at the blood-brain barrier, and a third as a result of the entrapment of copper in peripheral tissues. The copper deficiency results in demylenation and other major neurological defects in these patients that are probably responsible for the fatal outcome of this disorder.

0 0

Post a comment