Regulation of Copper Absorption and Excretion

The regulation of overall copper status of the body occurs by modification of the amount of dietary copper absorbed and the amount excreted in the bile. The uptake of dietary copper in the small intestine involves several main steps, each of which is a site of potential regulation: uptake, distribution and storage within the cell, and efflux across the basolateral membrane. The amount of copper absorbed from the diet has been found to depend on the copper content of the diet: When the dietary copper intake is very low, a high percentage is absorbed, and the amount absorbed is reduced as the copper content of the diet increases (34). The molecular basis of this regulation is unclear, but a model can be proposed for the mechanism of copper uptake based on current knowledge of the components of cellular copper transport (Fig. 3A). It is possible that the main method of copper entry into the enterocyte involves hCTR1, which is expressed in the small intestine (16). However, rats maintained on a diet containing only trace amounts of copper (<0.05 mg/kg) showed no increase in the level of CTR1 mRNA in intestinal mucosa, suggesting that regulation of copper uptake does not involve changes in transcription of the CTR1 gene. It is possible that copper regulation of CTR1 may occur by changes in location or levels of the protein, as in the Cu-dependent degradation of Ctr1p in S. cerevisiae (35). Alternatively, the regulation of Cu uptake in response to copper availability may involve CTR1-independent mechanisms. For example, other transporters may contribute to copper uptake, such as the broad-specificity metal-ion transporter Nramp2 (36), but such a system would not appear to have the specificity required for responses to changes in dietary intake of copper alone. High levels of dietary copper will induce the synthesis of metallothioneins to sequester the excess cytoplasmic copper. The metallothioneins may buffer the absorption of the metal, with the excess copper being eliminated when the epithelial cell is sloughed into the gut lumen. Such a mechanism has been suggested to underlie the reduction of copper absorption by high doses of zinc (37) used as a treatment for Wilson's disease (38).

The transfer of copper across the basolateral membrane requires ATP7A, and as indicated in Fig. 3B, patients with Menkes disease accumulate copper in the enterocyte because this step is blocked. The copper then becomes associated with metallothioneins and is presumably lost when the enterocyte is sloughed off. The role, if any, of ATP7A in the normal regulation of copper uptake is unclear. The known copper-induced trafficking of the protein to the plasma membrane (32) would suggest that

Fig. 3. (A) Model of copper transport in an intestinal enterocyte. Copper enters the cells via hCTR1 and it is possible that regulation of copper uptake is mediated by changes in the concentration or location of hCTR1. As with other cells, the copper is distributed within the cell by copper chaperones, but presumably a major pathway will be to ATP7A for the secretion of copper across the basolateral membrane. There is no definitive data on whether copper induces the movement of ATP7A to the basolateral membrane, but this is probable. It is not known whether the trafficking of ATP7A plays a part in regulating the amount of copper absorbed from the diet. (B) Model of copper transport in the enterocyte of an individual with Menkes disease. The absence of an active ATP7A results in accumulation of copper in the cell, as basolateral transport is not possible. The excess copper induces the transcription of MTs, which sequester the excess metal. This copper is lost to the body when the enterocyte sloughs off.

Fig. 3. (A) Model of copper transport in an intestinal enterocyte. Copper enters the cells via hCTR1 and it is possible that regulation of copper uptake is mediated by changes in the concentration or location of hCTR1. As with other cells, the copper is distributed within the cell by copper chaperones, but presumably a major pathway will be to ATP7A for the secretion of copper across the basolateral membrane. There is no definitive data on whether copper induces the movement of ATP7A to the basolateral membrane, but this is probable. It is not known whether the trafficking of ATP7A plays a part in regulating the amount of copper absorbed from the diet. (B) Model of copper transport in the enterocyte of an individual with Menkes disease. The absence of an active ATP7A results in accumulation of copper in the cell, as basolateral transport is not possible. The excess copper induces the transcription of MTs, which sequester the excess metal. This copper is lost to the body when the enterocyte sloughs off.

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