Copper induces hepatocyte injury due to the endoplasmic reticulum stress in cultured cells and patients with Wilson disease

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• 作者：Shinji Oe ; ¹ ; ^{ooes@med.uoeh-u.ac.jp" class="auth_mail" title="E-mail the corresponding author} ; Koichiro Miyagawa ^{koichiro@med.uoeh-u.ac.jp" class="auth_mail" title="E-mail the corresponding author} ; Yuichi Honma ^{y-homma@med.uoeh-u.ac.jp" class="auth_mail" title="E-mail the corresponding author} ; Masaru Harada ; ¹ ; ^{msrharada@med.uoeh-u.ac.jp" class="auth_mail" title="E-mail the corresponding author}
• 关键词：ALLN ; acetyl-leucyl-leucyl-norleucinal ; ATF6 ; activating transcription factor 6 ; BCS ; bathocuproine disulfonate ; ER ; endoplasmic reticulum ; GO ; glucose oxidase ; HCC ; hepatocellular carcinoma ; H2DCFDA ; 2&prime ; 7&prime ; -dichlorodihydrofluorescein diacetate ; IRE1α ; inositol-requiring 1α ; NAC ; n-acetyl-l-cysteine ; PARP ; poly-ADP-ribose-polymerase ; PBA ; 4-phenylbutyrate ; PBS ; phosphate-buffered saline ; p-eIF2α ; phospho-α-subunit of eukaryotic initiation factor 2 ; PERK ; protein kinase RNA-like endopl
• 刊名：Experimental Cell Research
• 出版年：2016
• 出版时间：10 September 2016
• 年：2016
• 卷：347
• 期：1
• 页码：192-200
• 全文大小：4024 K

文摘

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.