Intestinal regulation of copper homeostasis: a developmental perspective.
Stable-isotope studies in human infants and adults have shown that copper homeostasis occurs, but the contribution of the small intestine to this regulation is still not well understood. Copper first needs to be reduced to the cuprous form, most likely by Steap proteins on the apical membrane. Copper is subsequently absorbed by Ctr1 and then transferred in the enterocyte by the chaperone Atox1 to reach ATP7A for export from the cell. The role of ATP7B, shown to be present in the small intestine, is still poorly understood. In situations of high copper exposure, Ctr1 is endocytosed, metallothionein is induced, and ATP7A moves to a more basolateral localization. However, the ontogeny of regulation of copper homeostasis has received little attention. In rat pups, tissue copper and total-body (67)Cu retention decrease throughout postnatal development, whereas liver (67)Cu retention, serum copper, and ceruloplasmin activity increase. Total (67)Cu absorption decreases and intestinal (67)Cu retention increases with increased copper intake. During early infancy (day 10), copper supplementation increases intestinal copper and metallothionein gene expression, and Ctr1 protein levels increase, whereas Atp7A and Atp7B are unaffected. However, during late infancy (day 20), intestinal copper concentrations are unaffected by supplementation, but Ctr1, ATP7A, and Atp7B protein levels are higher than in controls. Thus, maturation of small intestine copper transport occurs through increased abundance and altered localization of Ctr1, Atp7A, and Atp7B. The mechanisms behind this maturation, including both transcriptional and posttranscriptional regulation, require further studies.
Lönnerdal
Bo
B
Department of Nutrition, University of California, Davis, CA 95616, USA. bllonnerdal@ucdavis.edu
D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D000833:Animals, Suckling / Q000378:metabolism; D001692:Biological Transport; D018938:Caco-2 Cells / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D027682:Cation Transport Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D003300:Copper / Q000172:deficiency / Q000378:metabolism* / Q000494:pharmacology; D000073840:Copper-Transporting ATPases; D006706:Homeostasis; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000254:growth & development; D051381:Rats
D002352:Carrier Proteins; D027682:Cation Transport Proteins; D003300:Copper; D000251:Adenosine Triphosphatases; C081184:ATP7A protein, human; D000073840:Copper-Transporting ATPases