title: Copper incorporation into ceruloplasmin is regulated by Niemann-Pick C1 protein.
abstract: OBJECTIVE
  Wilson disease is a genetic disorder of copper metabolism characterized by impaired biliary copper excretion. Wilson disease gene product (ATP7B) functions in copper incorporation to ceruloplasmin (Cp) and biliary copper excretion. Our previous study showed the late endosome localization of ATP7B and described the copper transport pathway from the late endosome to trans-Golgi network (TGN). However, the cellular localization of ATP7B and copper metabolism in hepatocytes remains controversial. The present study was performed to evaluate the role of Niemann-Pick type C (NPC) gene product NPC1 on intracellular copper transport in hepatocytes.
  
  
  METHODS
  We induced the NPC phenotype using U18666A to modulate the vesicle traffic from the late endosome to TGN. Then, we examined the effect of NPC1 overexpression on the localization of ATP7B and secretion of holo-Cp, a copper-binding mature form of Cp.
  
  
  RESULTS
  Overexpression of NPC1 increased holo-Cp secretion to culture medium of U18666A-treated cells, but did not affect the secretion of albumin. Manipulation of NPC1 function affected the localization of ATP7B and late endosome markers, but did not change the localization of a TGN marker. ATP7B co-localized with the late endosome markers, but not with the TGN marker.
  
  
  CONCLUSIONS
  These findings suggest that ATP7B localizes in the late endosomes and that copper in the late endosomes is transported to the secretory compartment via an NPC1-dependent pathway and incorporated into Cp.
authors.affiliation: Division of Gastroenterology, Department of Medicine and Research Center for Innovative Cancer Therapy of the 21st Century COE Program for Medical Science, Kurume University School of Medicine, Kurume Yanagimoto-naika, Itoshima The Third Department of Internal Medicine, University of Occupational and Environmental Health, Japan School of Medicine, Kitakyushu Department of Medicine, Onoba Hospital Biochemistry, Akita University School of Medicine, Akita Department of Neurobiology, Tottori University Faculty of Medicine, Yonago, Japan.
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authors.lastname: Hanada
authors.forename: Eitaro
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authors.lastname: Taniguchi
authors.forename: Haruaki
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authors.lastname: Ninomiya
authors.forename: Takato
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authors.lastname: Ueno
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Sugiyama
authors.forename: Michio
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authors.lastname: Sata