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Gastroenterology. 2000 Sep;119(3):782-93.

Copper-induced apical trafficking of ATP7B in polarized hepatoma cells provides a mechanism for biliary copper excretion.

Author information

1
Groningen University Institute for Drug Exploration (GUIDE), Center for Liver, Digestive and Metabolic Diseases, University Hospital Groningen, Groningen, The Netherlands. j.roelofsen@med.rug.nl

Abstract

BACKGROUND & AIMS:

Mutations in the ATP7B gene, encoding a copper-transporting P-type adenosine triphosphatase, lead to excessive hepatic copper accumulation because of impaired biliary copper excretion in Wilson's disease. In human liver, ATP7B is predominantly localized to the trans-Golgi network, which appears incompatible with a role of ATP7B in biliary copper excretion. The aim of this study was to elucidate this discrepancy.

METHODS:

Immunofluorescence and electron-microscopic methods were used to study the effects of excess copper on ATP7B localization in polarized HepG2 hepatoma cells.

RESULTS:

ATP7B is localized to the trans-Golgi network only when extracellular copper concentration is low (<1 micromol/L). At increased copper levels, ATP7B redistributes to vesicular structures and to apical vacuoles reminiscent of bile canaliculi. After copper depletion, ATP7B returns to the trans-Golgi network. Brefeldin A and nocodazole impair copper-induced apical trafficking of ATP7B and cause accumulation of apically retrieved transporters in a subapical compartment, suggesting continuous recycling of ATP7B between this vesicular compartment and the apical membrane when copper is increased.

CONCLUSIONS:

Copper induces trafficking of its own transporter from the trans-Golgi network to the apical membrane, where it may facilitate biliary copper excretion. This system of ligand-induced apical sorting provides a novel mechanism to control copper homeostasis in hepatic cells.

PMID:
10982773
[Indexed for MEDLINE]

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