Get access

Copper incorporation into ceruloplasmin is regulated by Niemann–Pick C1 protein

Authors

  • Chikatoshi Yanagimoto,

    Corresponding author
    1. 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
    2. Yanagimoto-naika, Itoshima
      Dr. Chikatoshi Yanagimoto, Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, 67 Asahi-Machi, Kurume 830-0011, Japan. Email: yanagimoto_chikatoshi@kurume-u.ac.jp
    Search for more papers by this author
  • Masaru Harada,

    1. The Third Department of Internal Medicine, University of Occupational and Environmental Health, Japan School of Medicine, Kitakyushu
    Search for more papers by this author
  • Hiroto Kumemura,

    1. 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
    Search for more papers by this author
  • Mitsuhiko Abe,

    1. 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
    Search for more papers by this author
  • Hironori Koga,

    1. 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
    Search for more papers by this author
  • Masahiro Sakata,

    1. 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
    Search for more papers by this author
  • Takumi Kawaguchi,

    1. 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
    Search for more papers by this author
  • Kunihiko Terada,

    1. Department of Medicine, Onoba Hospital
    Search for more papers by this author
  • Shinichiro Hanada,

    1. 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
    Search for more papers by this author
  • Eitaro Taniguchi,

    1. 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
    Search for more papers by this author
  • Haruaki Ninomiya,

    1. Department of Neurobiology, Tottori University Faculty of Medicine, Yonago, Japan
    Search for more papers by this author
  • Takato Ueno,

    1. 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
    Search for more papers by this author
  • Toshihiro Sugiyama,

    1. Biochemistry, Akita University School of Medicine, Akita
    Search for more papers by this author
  • Michio Sata

    1. 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
    Search for more papers by this author

Dr. Chikatoshi Yanagimoto, Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, 67 Asahi-Machi, Kurume 830-0011, Japan. Email: yanagimoto_chikatoshi@kurume-u.ac.jp

Abstract

Aim:  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.

Conclusion:  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.

Get access to the full text of this article

Ancillary