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

被引:219
作者
Roelofsen, H
Wolters, H
Van Luyn, MJA
Miura, N
Kuipers, F
Vonk, RJ
机构
[1] Univ Groningen Hosp, Dept Pediat, Ctr Liver Digest & Metab Dis, Groningen Univ Inst Drug Explorat, NL-9713 GZ Groningen, Netherlands
[2] Univ Groningen Hosp, Dept Med Biol, Ctr Liver Digest & Metab Dis, Groningen Univ Inst Drug Explorat, NL-9713 GZ Groningen, Netherlands
[3] Hamamatsu Univ Sch Med, Dept Biochem, Hamamatsu, Shizuoka 43131, Japan
关键词
D O I
10.1053/gast.2000.17834
中图分类号
R57 [消化系及腹部疾病];
学科分类号
摘要
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 mu mol/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.
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页码:782 / 793
页数:12
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