{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T14:46:50Z","timestamp":1790693210473,"version":"4.1.0"},"reference-count":46,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2018,12,18]],"date-time":"2018-12-18T00:00:00Z","timestamp":1545091200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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 \u00b1 1.8 vs. 11.1 \u00b1 0.8 nmol MDA\/g liver, p &lt; 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 \u00b1 1.5 vs. 5.4 \u00b1 0.9 \u00b5mol GSH\/g liver, p &lt; 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.<\/jats:p>","DOI":"10.3390\/ijms19124114","type":"journal-article","created":{"date-parts":[[2018,12,18]],"date-time":"2018-12-18T11:09:21Z","timestamp":1545131361000},"page":"4114","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":47,"title":["Tunicamycin-Induced ER Stress is Accompanied with Oxidative Stress via Abrogation of Sulfur Amino Acids Metabolism in the Liver"],"prefix":"10.3390","volume":"19","author":[{"given":"Sou Hyun","family":"Kim","sequence":"first","affiliation":[{"name":"College of Pharmacy, Pusan National University, Busan 46241, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Do-young","family":"Kwon","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA 94158-2280, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jae-Hwan","family":"Kwak","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Brain Busan 21 Plus Program, Kyungsung University, Busan 48434, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seunghyun","family":"Lee","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Pusan National University, Busan 46241, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun-Hee","family":"Lee","sequence":"additional","affiliation":[{"name":"College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jieun","family":"Yun","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Engineering, Cheongju University, Cheongju 28503, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tae Gen","family":"Son","sequence":"additional","affiliation":[{"name":"Division for Research Center, Dongnam Institute of Radiological and Medical Science, Busan 46033, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Young-Suk","family":"Jung","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Pusan National University, Busan 46241, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2018,12,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1592","DOI":"10.1053\/j.gastro.2012.04.001","article-title":"The diagnosis and management of non-alcoholic fatty liver disease: Practice guideline by the American Gastroenterological Association, American Association for the Study of Liver Diseases, and American College of Gastroenterology","volume":"142","author":"Chalasani","year":"2012","journal-title":"Gastroenterology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"686","DOI":"10.1038\/nrgastro.2013.171","article-title":"The global NAFLD epidemic","volume":"10","author":"Loomba","year":"2013","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1016\/j.cgh.2014.04.014","article-title":"Fibrosis progression in nonalcoholic fatty liver vs nonalcoholic steatohepatitis: A systematic review and meta-analysis of paired-biopsy studies","volume":"13","author":"Singh","year":"2015","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1172\/JCI200422422","article-title":"Molecular mediators of hepatic steatosis and liver injury","volume":"114","author":"Browning","year":"2004","journal-title":"J. Clin. Investig."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1519","DOI":"10.1126\/science.1204265","article-title":"Human fatty liver disease: Old questions and new insights","volume":"332","author":"Cohen","year":"2011","journal-title":"Science"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"842","DOI":"10.1016\/S0016-5085(98)70599-2","article-title":"Steatohepatitis: A tale of two \"hits\"?","volume":"114","author":"Day","year":"1998","journal-title":"Gastroenterology"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"927","DOI":"10.1016\/j.jhep.2018.06.008","article-title":"Endoplasmic reticulum stress signalling and the pathogenesis of non-alcoholic fatty liver disease","volume":"69","author":"Lebeaupin","year":"2018","journal-title":"J. Hepatol."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Ghemrawi, R., Battaglia-Hsu, S.F., and Arnold, C. (2018). Endoplasmic Reticulum Stress in Metabolic Disorders. Cells, 7.","DOI":"10.20944\/preprints201805.0264.v1"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"e180","DOI":"10.1111\/liv.12523","article-title":"Are oxidative stress mechanisms the common denominator in the progression from hepatic steatosis towards non-alcoholic steatohepatitis (NASH)?","volume":"34","author":"Tariq","year":"2014","journal-title":"Liver Int."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1297","DOI":"10.1016\/j.cca.2011.04.013","article-title":"The role of oxidative stress in non-alcoholic steatohepatitis","volume":"412","author":"Koek","year":"2011","journal-title":"Clin. Chim. Acta"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Del Ben, M., Polimeni, L., Carnevale, R., Bartimoccia, S., Nocella, C., Baratta, F., Loffredo, L., Pignatelli, P., Violi, F., and Angelico, F. (2014). NOX2-generated oxidative stress is associated with severity of ultrasound liver steatosis in patients with non-alcoholic fatty liver disease. BMC Gastroenterol., 14.","DOI":"10.1186\/1471-230X-14-81"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"S20","DOI":"10.1111\/j.1440-1746.2006.04640.x","article-title":"Role of mitochondria in non-alcoholic fatty liver disease","volume":"22","author":"Pessayre","year":"2007","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"964","DOI":"10.1016\/j.jhep.2010.09.022","article-title":"Intracellular reactive oxygen species are required for directional migration of resident and bone marrow-derived hepatic pro-fibrogenic cells","volume":"54","author":"Novo","year":"2011","journal-title":"J. Hepatol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1432","DOI":"10.1111\/j.1478-3231.2011.02604.x","article-title":"Antioxidants as therapeutic agents for liver disease","volume":"31","author":"Singal","year":"2011","journal-title":"Liver Int."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1146\/annurev-pathol-012615-044224","article-title":"Nonalcoholic Fatty Liver Disease: Pathogenesis and Disease Spectrum","volume":"11","author":"Hardy","year":"2016","journal-title":"Annu. Rev. Pathol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1089\/ars.2016.6776","article-title":"Oxidative Stress as a Critical Factor in Nonalcoholic Fatty Liver Disease Pathogenesis","volume":"26","author":"Spahis","year":"2017","journal-title":"Antioxid. Redox Signal."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3066","DOI":"10.1101\/gad.1250704","article-title":"CHOP induces death by promoting protein synthesis and oxidation in the stressed endoplasmic reticulum","volume":"18","author":"Marciniak","year":"2004","journal-title":"Genes Dev."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1016\/j.cell.2005.11.040","article-title":"Endoplasmic reticulum stress activates cleavage of CREBH to induce a systemic inflammatory response","volume":"124","author":"Zhang","year":"2006","journal-title":"Cell"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1016\/j.devcel.2008.10.015","article-title":"UPR pathways combine to prevent hepatic steatosis caused by ER stress-mediated suppression of transcriptional master regulators","volume":"15","author":"Rutkowski","year":"2008","journal-title":"Dev. Cell"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2975","DOI":"10.1091\/mbc.e09-02-0133","article-title":"Induction of liver steatosis and lipid droplet formation in ATF6alpha-knockout mice burdened with pharmacological endoplasmic reticulum stress","volume":"21","author":"Yamamoto","year":"2010","journal-title":"Mol. Biol. Cell"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1357","DOI":"10.1038\/emboj.2011.52","article-title":"The unfolded protein response transducer IRE1alpha prevents ER stress-induced hepatic steatosis","volume":"30","author":"Zhang","year":"2011","journal-title":"EMBO J."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1016\/j.mce.2014.04.012","article-title":"Resolvin D1 reduces ER stress-induced apoptosis and triglyceride accumulation through JNK pathway in HepG2 cells","volume":"391","author":"Jung","year":"2014","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1002\/jcb.22996","article-title":"ACSL3 and GSK-3beta are essential for lipid upregulation induced by endoplasmic reticulum stress in liver cells","volume":"112","author":"Chang","year":"2011","journal-title":"J. Cell. Biochem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1038\/nature08111","article-title":"The CREB coactivator CRTC2 links hepatic ER stress and fasting gluconeogenesis","volume":"460","author":"Wang","year":"2009","journal-title":"Nature"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Feng, B., Huang, X., Jiang, D., Hua, L., Zhuo, Y., and Wu, D. (2017). Endoplasmic Reticulum Stress Inducer Tunicamycin Alters Hepatic Energy Homeostasis in Mice. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18081710"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1016\/B978-0-12-385116-1.00019-4","article-title":"Measurement of ER stress response and inflammation in the mouse model of nonalcoholic fatty liver disease","volume":"489","author":"Zheng","year":"2011","journal-title":"Methods Enzymol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.toxlet.2012.02.017","article-title":"Pharmacologic ER stress induces non-alcoholic steatohepatitis in an animal model","volume":"211","author":"Lee","year":"2012","journal-title":"Toxicol. Lett."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1053\/j.gastro.2015.09.039","article-title":"Endoplasmic Reticulum Stress in Hepatic Stellate Cells Promotes Liver Fibrosis via PERK-Mediated Degradation of HNRNPA1 and Up-regulation of SMAD2","volume":"150","author":"Koo","year":"2016","journal-title":"Gastroenterology"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"971","DOI":"10.1248\/bpb.b15-00244","article-title":"Metabolism of Sulfur-Containing Amino Acids in the Liver: A Link between Hepatic Injury and Recovery","volume":"38","author":"Jung","year":"2015","journal-title":"Biol. Pharm. Bull."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Lee, Y.H., Kim, S.H., Lee, S., Kim, K.M., Jung, J.C., Son, T.G., Ki, S.H., Seo, W.D., Kwak, J.H., and Hong, J.T. (2017). Antioxidant Effect of Barley Sprout Extract via Enhancement of Nuclear Factor-Erythroid 2 Related Factor 2 Activity and Glutathione Synthesis. Nutrients, 9.","DOI":"10.3390\/nu9111252"},{"key":"ref_31","first-page":"2011","article-title":"Transformation of liver cells by 3-methylcholanthrene potentiates oxidative stress via the downregulation of glutathione synthesis","volume":"40","author":"Kim","year":"2017","journal-title":"Int. J. Mol. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1089\/ars.2014.5851","article-title":"Endoplasmic reticulum stress and oxidative stress in cell fate decision and human disease","volume":"21","author":"Cao","year":"2014","journal-title":"Antioxid. Redox Signal."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1463","DOI":"10.1002\/hep.510270601","article-title":"Hepatic steatosis: Innocent bystander or guilty party?","volume":"27","author":"Day","year":"1998","journal-title":"Hepatology"},{"key":"ref_34","first-page":"9038","article-title":"Translational approaches: From fatty liver to non-alcoholic steatohepatitis","volume":"20","author":"Rosso","year":"2014","journal-title":"World J. Gastroenterol."},{"key":"ref_35","first-page":"221","article-title":"Molecular pathways in non-alcoholic fatty liver disease","volume":"7","author":"Berlanga","year":"2014","journal-title":"Clin. Exp. Gastroenterol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1707","DOI":"10.1016\/j.drudis.2017.06.007","article-title":"Mouse models of nonalcoholic steatohepatitis in preclinical drug development","volume":"22","author":"Hansen","year":"2017","journal-title":"Drug Discov. Today"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1038","DOI":"10.1016\/j.metabol.2015.12.012","article-title":"The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD)","volume":"65","author":"Buzzetti","year":"2016","journal-title":"Metabolism"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"869","DOI":"10.3109\/10715762.2013.837577","article-title":"Involvement of free radicals and oxidative stress in NAFLD\/NASH","volume":"47","author":"Sumida","year":"2013","journal-title":"Free Radic. Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"924","DOI":"10.1177\/147323001204000311","article-title":"Levels of the oxidative stress marker gamma-glutamyltranspeptidase at different stages of nonalcoholic fatty liver disease","volume":"40","author":"Irie","year":"2012","journal-title":"J. Int. Med. Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1010","DOI":"10.1111\/j.1440-1746.2011.06672.x","article-title":"Plasma reactive carbonyl species levels and risk of non-alcoholic fatty liver disease","volume":"26","author":"Liu","year":"2011","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"471","DOI":"10.3892\/ijmm_00000487","article-title":"Oxidative stress parameters in paediatric non-alcoholic fatty liver disease","volume":"26","author":"Nobili","year":"2010","journal-title":"Int. J. Mol. Med."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"33","DOI":"10.4274\/Jcrpe.825","article-title":"Association between insulin resistance and oxidative stress parameters in obese adolescents with non-alcoholic fatty liver disease","volume":"5","author":"Pirgon","year":"2013","journal-title":"J. Clin. Res. Pediatr. Endocrinol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"913","DOI":"10.1016\/j.bbrc.2008.02.005","article-title":"Comparison of the effects of buthioninesulfoximine and phorone on the metabolism of sulfur-containing amino acids in rat liver","volume":"368","author":"Jung","year":"2008","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1016\/S0378-4347(98)00195-9","article-title":"Improvement in the high-performance liquid chromatography malondialdehyde level determination in normal human plasma","volume":"713","author":"Volpi","year":"1998","journal-title":"J. Chromatogr. B Biomed. Sci. Appl."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1016\/S0378-4347(97)00128-X","article-title":"Simple high-performance liquid chromatographic method for assaying cysteinesulfinic acid decarboxylase activity in rat tissue","volume":"694","author":"Ide","year":"1997","journal-title":"J. Chromatogr. B Biomed. Sci. Appl."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"554","DOI":"10.1016\/j.jchromb.2007.02.024","article-title":"Simultaneous determination of total homocysteine, cysteine, cysteinylglycine, and glutathione in human plasma by high-performance liquid chromatography: Application to studies of oxidative stress","volume":"852","author":"Nolin","year":"2007","journal-title":"J. Chromatogr. B Anal. Technol. Biomed. Life Sci."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/19\/12\/4114\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T15:34:47Z","timestamp":1760196887000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/19\/12\/4114"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,12,18]]},"references-count":46,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2018,12]]}},"alternative-id":["ijms19124114"],"URL":"https:\/\/doi.org\/10.3390\/ijms19124114","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,12,18]]}}}