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

Gastroenterology. 2000 Sep;119(3):782-93. doi: 10.1053/gast.2000.17834.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphatases / metabolism*
  • Bile / metabolism*
  • Biological Transport / drug effects
  • Carcinoma, Hepatocellular / metabolism*
  • Carcinoma, Hepatocellular / pathology
  • Carrier Proteins / metabolism*
  • Cation Transport Proteins*
  • Cell Membrane / metabolism
  • Cell Polarity
  • Copper / metabolism*
  • Copper / pharmacology*
  • Copper-Transporting ATPases
  • Fluorescent Antibody Technique
  • Golgi Apparatus / metabolism
  • Humans
  • Liver Neoplasms / metabolism*
  • Liver Neoplasms / pathology
  • Microscopy, Electron
  • Tumor Cells, Cultured


  • Carrier Proteins
  • Cation Transport Proteins
  • Copper
  • Adenosine Triphosphatases
  • ATP7B protein, human
  • Copper-Transporting ATPases