title: Copper induces hepatocyte injury due to the endoplasmic reticulum stress in cultured cells and patients with Wilson disease.
abstract: Copper is an essential trace element, however, excess copper is harmful to human health. Excess copper-derived oxidants contribute to the progression of Wilson disease, and oxidative stress induces accumulation of abnormal proteins. It is known that the endoplasmic reticulum (ER) plays an important role in proper protein folding, and that accumulation of misfolded proteins disturbs ER homeostasis resulting in ER stress. However, copper-induced ER homeostasis disturbance has not been fully clarified. We treated human hepatoma cell line (Huh7) and immortalized-human hepatocyte cell line (OUMS29) with copper and chemical chaperones, including 4-phenylbutyrate and ursodeoxycholic acid. We examined copper-induced oxidative stress, ER stress and apoptosis by immunofluorescence microscopy and immunoblot analyses. Furthermore, we examined the effects of copper on carcinogenesis. Excess copper induced not only oxidative stress but also ER stress. Furthermore, excess copper induced DNA damage and reduced cell proliferation. Chemical chaperones reduced this copper-induced hepatotoxicity. Excess copper induced hepatotoxicity via ER stress. We also confirmed the abnormality of ultra-structure of the ER of hepatocytes in patients with Wilson disease. These findings show that ER stress plays a pivotal role in Wilson disease, and suggests that chemical chaperones may have beneficial effects in the treatment of Wilson disease.
authors: Third Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan. Electronic address: ooes@med.uoeh-u.ac.jp.
authors: Shinji
authors: S
authors: Oe
authors: Third Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan. Electronic address: koichiro@med.uoeh-u.ac.jp.
authors: Koichiro
authors: K
authors: Miyagawa
authors: Third Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan. Electronic address: y-homma@med.uoeh-u.ac.jp.
authors: Yuichi
authors: Y
authors: Honma
authors: Third Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan. Electronic address: msrharada@med.uoeh-u.ac.jp.
authors: Masaru
authors: M
authors: Harada
mesh_terms: D000328:Adult; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003300:Copper / Q000633:toxicity*; D004249:DNA Damage; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D005260:Female; D005455:Fluorescent Antibody Technique; D057809:HEK293 Cells; D022781:Hepatocytes / Q000187:drug effects / Q000473:pathology*; D006527:Hepatolenticular Degeneration / Q000473:pathology*; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D015151:Immunoblotting; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D018384:Oxidative Stress / Q000187:drug effects; D061988:Proteasome Inhibitors / Q000494:pharmacology; D019345:Zinc Acetate / Q000494:pharmacology
chemical_list: D019394:Ki-67 Antigen; D061988:Proteasome Inhibitors; D003300:Copper; D006861:Hydrogen Peroxide; D053148:Caspase 3; D019345:Zinc Acetate
keywords: Chemical chaperone; Copper; Endoplasmic reticulum stress; Wilson disease; Zinc