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Am J Physiol Gastrointest Liver Physiol (February 26, 2004). doi:10.1152/ajpgi.00297.2003
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Submitted on July 16, 2003
Accepted on February 20, 2004

Copper overload affects copper and iron metabolism in HepG2 cells

M Arredondo1, V Cambiazo2, L Tapia2, M Gonzalez-Aguero2, M T Nunez3, R Uauy1, and M Gonzalez2*

1 Microminerals Laboratory, Institute of Nutrition and Food Technology (INTA), University of Chile, Santiago, Chile
2 Bioinformatic and Gene Expression Laboratory, Institute of Nutrition and Food Technology (INTA), University of Chile, Santiago, Chile
3 Department of Biology, Faculty of Science, University of Chile, Santiago, Chile

* To whom correspondence should be addressed. E-mail: mgonzale{at}inta.cl.

DMT1 transporter is responsible for intestinal non-heme Fe apical uptake. However, DMT1 appears to have an additional function in Cu transport in intestinal cells. Since the liver has an essential role in body Cu homeostasis, we examined the potential involvement of Cu in the regulation of DMT1 expression and activity in HepG2 cells. Cells exposed to 10 µM Cu exhibited a 22-fold increase in Cu content, and a 2-fold decrease in Fe content compared with cells maintained in 0.4 µM Cu. 64Cu uptake in Cu-deficient HepG2 cells showed a 2- fold decrease in Km compared to cells grown in 10 µM Cu. The decreased Km may represent an adaptive response to Cu-deficiency. Cells treated with >50 µM Cu, showed an 8-fold increase in cytosolic metallothionein. DMT1 protein decreased (35%), suggesting that intracellular Cu caused a reduction of DMT1 protein levels. Our data indicate that as a result of Cu overload HepG2 cells reduced their Fe content and their DMT1 protein levels. These findings strongly suggest a relationship between Cu and Fe homeostasis in HepG2 cells in which Cu accumulation down-regulates DMT1 activity.




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