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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:
; ; ;
Publication Date:
OSTI Identifier:
22649760
Resource Type:
Journal Article
Resource Relation:
Journal Name: Experimental Cell Research; Journal Volume: 347; Journal Issue: 1; Other Information: Copyright (c) 2016 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; APOPTOSIS; CARCINOGENESIS; CELL CULTURES; CELL PROLIFERATION; COPPER; CYSTEINE; DNA DAMAGES; ENDOPLASMIC RETICULUM; GLUCOSE; HEPATOMAS; HOMEOSTASIS; INJURIES; INOSITOL; LIVER CELLS; OXIDASES; OXIDIZERS; PATIENTS; PHOSPHATES; PHOSPHOTRANSFERASES; POLYMERASES; PUBLIC HEALTH; RIBOSE; RNA; TRACE AMOUNTS; TRANSCRIPTION; TRANSCRIPTION FACTORS

Citation Formats

Oe, Shinji, E-mail: ooes@med.uoeh-u.ac.jp, Miyagawa, Koichiro, E-mail: koichiro@med.uoeh-u.ac.jp, Honma, Yuichi, E-mail: y-homma@med.uoeh-u.ac.jp, and Harada, Masaru, E-mail: msrharada@med.uoeh-u.ac.jp. Copper induces hepatocyte injury due to the endoplasmic reticulum stress in cultured cells and patients with Wilson disease. United States: N. p., 2016. Web. doi:10.1016/J.YEXCR.2016.08.003.
Oe, Shinji, E-mail: ooes@med.uoeh-u.ac.jp, Miyagawa, Koichiro, E-mail: koichiro@med.uoeh-u.ac.jp, Honma, Yuichi, E-mail: y-homma@med.uoeh-u.ac.jp, & Harada, Masaru, E-mail: msrharada@med.uoeh-u.ac.jp. Copper induces hepatocyte injury due to the endoplasmic reticulum stress in cultured cells and patients with Wilson disease. United States. doi:10.1016/J.YEXCR.2016.08.003.
Oe, Shinji, E-mail: ooes@med.uoeh-u.ac.jp, Miyagawa, Koichiro, E-mail: koichiro@med.uoeh-u.ac.jp, Honma, Yuichi, E-mail: y-homma@med.uoeh-u.ac.jp, and Harada, Masaru, E-mail: msrharada@med.uoeh-u.ac.jp. Sat . "Copper induces hepatocyte injury due to the endoplasmic reticulum stress in cultured cells and patients with Wilson disease". United States. doi:10.1016/J.YEXCR.2016.08.003.
@article{osti_22649760,
title = {Copper induces hepatocyte injury due to the endoplasmic reticulum stress in cultured cells and patients with Wilson disease},
author = {Oe, Shinji, E-mail: ooes@med.uoeh-u.ac.jp and Miyagawa, Koichiro, E-mail: koichiro@med.uoeh-u.ac.jp and Honma, Yuichi, E-mail: y-homma@med.uoeh-u.ac.jp and Harada, Masaru, E-mail: msrharada@med.uoeh-u.ac.jp},
abstractNote = {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.},
doi = {10.1016/J.YEXCR.2016.08.003},
journal = {Experimental Cell Research},
number = 1,
volume = 347,
place = {United States},
year = {Sat Sep 10 00:00:00 EDT 2016},
month = {Sat Sep 10 00:00:00 EDT 2016}
}