Cargando…

Tunicamycin-Induced ER Stress is Accompanied with Oxidative Stress via Abrogation of Sulfur Amino Acids Metabolism in the Liver

Endoplasmic reticulum (ER) stress is involved in non-alcoholic fatty liver disease (NAFLD), but the relationship between oxidative stress, another well-known risk factor of NAFLD, and ER stress has yet to be elucidated. In this study, we treated mice with tunicamycin (TM) (2 mg/kg body weight) for 4...

Descripción completa

Detalles Bibliográficos
Autores principales: Kim, Sou Hyun, Kwon, Do-young, Kwak, Jae-Hwan, Lee, Seunghyun, Lee, Yun-Hee, Yun, Jieun, Son, Tae Gen, Jung, Young-Suk
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6321199/
https://www.ncbi.nlm.nih.gov/pubmed/30567393
http://dx.doi.org/10.3390/ijms19124114
_version_ 1783385385142845440
author Kim, Sou Hyun
Kwon, Do-young
Kwak, Jae-Hwan
Lee, Seunghyun
Lee, Yun-Hee
Yun, Jieun
Son, Tae Gen
Jung, Young-Suk
author_facet Kim, Sou Hyun
Kwon, Do-young
Kwak, Jae-Hwan
Lee, Seunghyun
Lee, Yun-Hee
Yun, Jieun
Son, Tae Gen
Jung, Young-Suk
author_sort Kim, Sou Hyun
collection PubMed
description Endoplasmic reticulum (ER) stress is involved in non-alcoholic fatty liver disease (NAFLD), but the relationship between oxidative stress, another well-known risk factor of NAFLD, and ER stress has yet to be elucidated. In this study, we treated mice with tunicamycin (TM) (2 mg/kg body weight) for 48 h to induce ER stress in the liver and examined the metabolic pathway that synthesizes the endogenous antioxidant, glutathione (GSH). Tunicamycin (TM) treatment significantly increased mRNA levels of CHOP and GRP78, and induced lipid accumulation in the liver. Lipid peroxidation in the liver tissue also increased from TM treatment (CON vs. TM; 3.0 ± 1.8 vs. 11.1 ± 0.8 nmol MDA/g liver, p < 0.001), which reflects an imbalance between the generation of reactive substances and antioxidant capacity. To examine the involvement of GSH synthetic pathway, we determined the metabolomic changes of sulfur amino acids in the liver. TM significantly decreased hepatic S-adenosylmethionine concentration in the methionine cycle. The levels of cysteine in the liver were increased, while taurine concentration was maintained and GSH levels profoundly decreased (CON vs. TM; 8.7 ± 1.5 vs. 5.4 ± 0.9 µmol GSH/g liver, p < 0.001). These results suggest that abnormal cysteine metabolism by TM treatment resulted in a decrease in GSH, followed by an increase in oxidative stress in the liver. In HepG2 cells, decreased GSH levels were examined by TM treatment in a dose dependent manner. Furthermore, pretreatment with TM in HepG2 cells potentiated oxidative cell death, by exacerbating the effects of tert-butyl hydroperoxide. In conclusion, TM-induced ER stress was accompanied by oxidative stress by reducing the GSH synthesis, which made the liver more susceptible to oxidative stress.
format Online
Article
Text
id pubmed-6321199
institution National Center for Biotechnology Information
language English
publishDate 2018
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-63211992019-01-07 Tunicamycin-Induced ER Stress is Accompanied with Oxidative Stress via Abrogation of Sulfur Amino Acids Metabolism in the Liver Kim, Sou Hyun Kwon, Do-young Kwak, Jae-Hwan Lee, Seunghyun Lee, Yun-Hee Yun, Jieun Son, Tae Gen Jung, Young-Suk Int J Mol Sci Article Endoplasmic reticulum (ER) stress is involved in non-alcoholic fatty liver disease (NAFLD), but the relationship between oxidative stress, another well-known risk factor of NAFLD, and ER stress has yet to be elucidated. In this study, we treated mice with tunicamycin (TM) (2 mg/kg body weight) for 48 h to induce ER stress in the liver and examined the metabolic pathway that synthesizes the endogenous antioxidant, glutathione (GSH). Tunicamycin (TM) treatment significantly increased mRNA levels of CHOP and GRP78, and induced lipid accumulation in the liver. Lipid peroxidation in the liver tissue also increased from TM treatment (CON vs. TM; 3.0 ± 1.8 vs. 11.1 ± 0.8 nmol MDA/g liver, p < 0.001), which reflects an imbalance between the generation of reactive substances and antioxidant capacity. To examine the involvement of GSH synthetic pathway, we determined the metabolomic changes of sulfur amino acids in the liver. TM significantly decreased hepatic S-adenosylmethionine concentration in the methionine cycle. The levels of cysteine in the liver were increased, while taurine concentration was maintained and GSH levels profoundly decreased (CON vs. TM; 8.7 ± 1.5 vs. 5.4 ± 0.9 µmol GSH/g liver, p < 0.001). These results suggest that abnormal cysteine metabolism by TM treatment resulted in a decrease in GSH, followed by an increase in oxidative stress in the liver. In HepG2 cells, decreased GSH levels were examined by TM treatment in a dose dependent manner. Furthermore, pretreatment with TM in HepG2 cells potentiated oxidative cell death, by exacerbating the effects of tert-butyl hydroperoxide. In conclusion, TM-induced ER stress was accompanied by oxidative stress by reducing the GSH synthesis, which made the liver more susceptible to oxidative stress. MDPI 2018-12-18 /pmc/articles/PMC6321199/ /pubmed/30567393 http://dx.doi.org/10.3390/ijms19124114 Text en © 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Kim, Sou Hyun
Kwon, Do-young
Kwak, Jae-Hwan
Lee, Seunghyun
Lee, Yun-Hee
Yun, Jieun
Son, Tae Gen
Jung, Young-Suk
Tunicamycin-Induced ER Stress is Accompanied with Oxidative Stress via Abrogation of Sulfur Amino Acids Metabolism in the Liver
title Tunicamycin-Induced ER Stress is Accompanied with Oxidative Stress via Abrogation of Sulfur Amino Acids Metabolism in the Liver
title_full Tunicamycin-Induced ER Stress is Accompanied with Oxidative Stress via Abrogation of Sulfur Amino Acids Metabolism in the Liver
title_fullStr Tunicamycin-Induced ER Stress is Accompanied with Oxidative Stress via Abrogation of Sulfur Amino Acids Metabolism in the Liver
title_full_unstemmed Tunicamycin-Induced ER Stress is Accompanied with Oxidative Stress via Abrogation of Sulfur Amino Acids Metabolism in the Liver
title_short Tunicamycin-Induced ER Stress is Accompanied with Oxidative Stress via Abrogation of Sulfur Amino Acids Metabolism in the Liver
title_sort tunicamycin-induced er stress is accompanied with oxidative stress via abrogation of sulfur amino acids metabolism in the liver
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6321199/
https://www.ncbi.nlm.nih.gov/pubmed/30567393
http://dx.doi.org/10.3390/ijms19124114
work_keys_str_mv AT kimsouhyun tunicamycininducederstressisaccompaniedwithoxidativestressviaabrogationofsulfuraminoacidsmetabolismintheliver
AT kwondoyoung tunicamycininducederstressisaccompaniedwithoxidativestressviaabrogationofsulfuraminoacidsmetabolismintheliver
AT kwakjaehwan tunicamycininducederstressisaccompaniedwithoxidativestressviaabrogationofsulfuraminoacidsmetabolismintheliver
AT leeseunghyun tunicamycininducederstressisaccompaniedwithoxidativestressviaabrogationofsulfuraminoacidsmetabolismintheliver
AT leeyunhee tunicamycininducederstressisaccompaniedwithoxidativestressviaabrogationofsulfuraminoacidsmetabolismintheliver
AT yunjieun tunicamycininducederstressisaccompaniedwithoxidativestressviaabrogationofsulfuraminoacidsmetabolismintheliver
AT sontaegen tunicamycininducederstressisaccompaniedwithoxidativestressviaabrogationofsulfuraminoacidsmetabolismintheliver
AT jungyoungsuk tunicamycininducederstressisaccompaniedwithoxidativestressviaabrogationofsulfuraminoacidsmetabolismintheliver