{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:52:01Z","timestamp":1760147521037,"version":"build-2065373602"},"reference-count":60,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2023,2,11]],"date-time":"2023-02-11T00:00:00Z","timestamp":1676073600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003725","name":"Medical Research Center Program","doi-asserted-by":"publisher","award":["2022R1A5A2018865","2021R1A2C1010851","2020R1I1A1A01072777"],"award-info":[{"award-number":["2022R1A5A2018865","2021R1A2C1010851","2020R1I1A1A01072777"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003725","name":"Basic Science Research Program","doi-asserted-by":"publisher","award":["2022R1A5A2018865","2021R1A2C1010851","2020R1I1A1A01072777"],"award-info":[{"award-number":["2022R1A5A2018865","2021R1A2C1010851","2020R1I1A1A01072777"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>TXNIP is a critical regulator of glucose homeostasis, fatty acid synthesis, and cholesterol accumulation in the liver, and it has been reported that metabolic diseases, such as obesity, atherosclerosis, hyperlipidemia, type 2 diabetes, and nonalcoholic fatty liver disease (NAFLD), are associated with endoplasmic reticulum (ER) stress. Because CHIP, an E3 ligase, was known to be involved in regulating tissue injury and inflammation in liver, its role in regulating ER stress-induced NAFLD was investigated in two experimental NAFLD models, a tunicamycin (TM)-induced and other diet-induced NAFLD mice models. In the TM-induced NAFLD model, intraperitoneal injection of TM induced liver steatosis in both CHIP+\/+ and CHIP+\/\u2212 mice, but it was severely exacerbated in CHIP+\/\u2212 mice compared to CHIP+\/+ mice. Key regulators of ER stress and de novo lipogenesis were also enhanced in the livers of TM-inoculated CHIP+\/\u2212 mice. Furthermore, in the diet-induced NAFLD models, CHIP+\/\u2212 mice developed severely impaired glucose tolerance, insulin resistance and hepatic steatosis compared to CHIP+\/+ mice. Interestingly, CHIP promoted ubiquitin-dependent degradation of TXNIP in vitro, and inhibition of TXNIP was further found to alleviate the inflammation and ER stress responses increased by CHIP inhibition. In addition, the expression of TXNIP was increased in mice deficient in CHIP in the TM- and diet-induced models. These findings suggest that CHIP modulates ER stress and inflammatory responses by inhibiting TXNIP, and that CHIP protects against TM- or HF\u2013HS diet-induced NAFLD and serves as a potential therapeutic means for treating liver diseases.<\/jats:p>","DOI":"10.3390\/antiox12020458","type":"journal-article","created":{"date-parts":[[2023,2,13]],"date-time":"2023-02-13T04:07:19Z","timestamp":1676261239000},"page":"458","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["CHIP Haploinsufficiency Exacerbates Hepatic Steatosis via Enhanced TXNIP Expression and Endoplasmic Reticulum Stress Responses"],"prefix":"10.3390","volume":"12","author":[{"given":"Jung-Hwa","family":"Han","sequence":"first","affiliation":[{"name":"PNU GRAND Convergence Medical Science Education Research Center, Pusan National University School of Medicine, Yangsan 50612, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dae-Hwan","family":"Nam","sequence":"additional","affiliation":[{"name":"Immune Research Institute, Seegene Medical Foundation, Seoul 04805, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Seon-Hui","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Yeungnam University College of Medicine, 170 Hyeonchung-ro, Nam-gu, Daegu 42415, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ae-Rang","family":"Hwang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Yeungnam University College of Medicine, 170 Hyeonchung-ro, Nam-gu, Daegu 42415, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"So-Young","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Physiology, Yeungnam University College of Medicine, 170 Hyeonchung-ro, Nam-gu, Daegu 42415, Republic of Korea"},{"name":"Senotherpy-Based Metabolic Disease Control Research Center, Yeungnam University College of Medicine, 170 Hyeonchung-ro, Nam-gu, Daegu 42415, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0972-9271","authenticated-orcid":false,"given":"Jae Hyang","family":"Lim","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Ewha Education and Research Center for Infection, Ewha Womans University College of Medicine, 25 Magokdong-ro 2-gil, Seoul 07804, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chang-Hoon","family":"Woo","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Yeungnam University College of Medicine, 170 Hyeonchung-ro, Nam-gu, Daegu 42415, Republic of Korea"},{"name":"Senotherpy-Based Metabolic Disease Control Research Center, Yeungnam University College of Medicine, 170 Hyeonchung-ro, Nam-gu, Daegu 42415, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1413","DOI":"10.1016\/S0016-5085(99)70506-8","article-title":"Nonalcoholic fatty liver disease: A spectrum of clinical and pathological severity","volume":"116","author":"Matteoni","year":"1999","journal-title":"Gastroenterology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1053\/gast.2002.34168","article-title":"Expanding the natural history of nonalcoholic steatohepatitis: From cryptogenic cirrhosis to hepatocellular carcinoma","volume":"123","author":"Bugianesi","year":"2002","journal-title":"Gastroenterology"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1016\/j.cgh.2011.03.020","article-title":"Changes in the prevalence of the most common causes of chronic liver diseases in the United States from 1988 to 2008","volume":"9","author":"Younossi","year":"2011","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1097\/MCG.0000000000000116","article-title":"World Gastroenterology Organisation global guidelines: Nonalcoholic fatty liver disease and nonalcoholic steatohepatitis","volume":"48","author":"Review","year":"2014","journal-title":"J. Clin. Gastroenterol."},{"key":"ref_5","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_6","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1177\/1535370215579161","article-title":"Nonalcoholic fatty liver disease: Update on pathogenesis, diagnosis, treatment and the role of S-adenosylmethionine","volume":"240","author":"Noureddin","year":"2015","journal-title":"Exp. Biol. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1007\/s00018-015-2052-6","article-title":"The endoplasmic reticulum: Structure, function and response to cellular signaling","volume":"73","author":"Schwarz","year":"2016","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"457","DOI":"10.14348\/molcells.2017.2296","article-title":"CHOP Deficiency Ameliorates ERK5 Inhibition-Mediated Exacerbation of Streptozotocin-Induced Hyperglycemia and Pancreatic \u03b2-Cell Apoptosis","volume":"40","author":"Nam","year":"2017","journal-title":"Mol. Cells"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1016\/j.yjmcc.2015.05.016","article-title":"CHOP deficiency prevents methylglyoxal-induced myocyte apoptosis and cardiac dysfunction","volume":"85","author":"Nam","year":"2015","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1038\/35014014","article-title":"Dynamic interaction of BiP and ER stress transducers in the unfolded-protein response","volume":"2","author":"Bertolotti","year":"2000","journal-title":"Nat. Cell Biol."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Shen, X., Ellis, R.E., Sakaki, K., and Kaufman, R.J. (2005). Genetic interactions due to constitutive and inducible gene regulation mediated by the unfolded protein response in C. elegans. PLoS Genet., 1.","DOI":"10.1371\/journal.pgen.0010037"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1146\/annurev.pathmechdis.3.121806.151434","article-title":"Endoplasmic reticulum stress in disease pathogenesis","volume":"3","author":"Lin","year":"2008","journal-title":"Annu. Rev. Pathol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1366","DOI":"10.1002\/hep.26126","article-title":"Endoplasmic reticulum stress induces hepatic steatosis via increased expression of the hepatic very low-density lipoprotein receptor","volume":"57","author":"Jo","year":"2013","journal-title":"Hepatology"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1161\/CIRCRESAHA.110.224766","article-title":"The role of endoplasmic reticulum stress in the progression of atherosclerosis","volume":"107","author":"Tabas","year":"2010","journal-title":"Circ. Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1042\/bj1980331","article-title":"Effect of tunicamycin on epidermal glycoprotein and glycosaminoglycan synthesis in vitro","volume":"198","author":"King","year":"1981","journal-title":"Biochem. J."},{"key":"ref_16","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_17","doi-asserted-by":"crossref","first-page":"F875","DOI":"10.1152\/ajprenal.00590.2012","article-title":"Gender differences control the susceptibility to ER stress-induced acute kidney injury","volume":"304","author":"Hodeify","year":"2013","journal-title":"Am. J. Physiol. Ren. Physiol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"21645","DOI":"10.1074\/jbc.274.31.21645","article-title":"Identification of thioredoxin-binding protein-2\/vitamin D(3) up-regulated protein 1 as a negative regulator of thioredoxin function and expression","volume":"274","author":"Nishiyama","year":"1999","journal-title":"J. Biol. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1089\/ars.2011.4137","article-title":"Thioredoxin interacting protein: Redox dependent and independent regulatory mechanisms","volume":"16","author":"Spindel","year":"2012","journal-title":"Antioxid Redox Signal."},{"key":"ref_20","first-page":"345","article-title":"Diverse functions of VDUP1 in cell proliferation, differentiation, and diseases","volume":"4","author":"Kim","year":"2007","journal-title":"Cell. Mol. Immunol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1352","DOI":"10.1111\/bph.12226","article-title":"Quercetin and allopurinol reduce liver thioredoxin-interacting protein to alleviate inflammation and lipid accumulation in diabetic rats","volume":"169","author":"Wang","year":"2013","journal-title":"Br. J. Pharm."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1016\/j.mito.2012.06.004","article-title":"Roles of thioredoxin binding protein (TXNIP) in oxidative stress, apoptosis and cancer","volume":"13","author":"Zhou","year":"2013","journal-title":"Mitochondrion"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"25168","DOI":"10.3390\/ijms161025168","article-title":"Relevant Aspects of Nutritional and Dietary Interventions in Non-Alcoholic Fatty Liver Disease","volume":"16","author":"Valenzuela","year":"2015","journal-title":"Int. J. Mol. Sci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"895","DOI":"10.1016\/j.dld.2020.04.019","article-title":"Suppression of high-fat diet-induced obesity-associated liver mitochondrial dysfunction by docosahexaenoic acid and hydroxytyrosol co-administration","volume":"52","author":"Ortiz","year":"2020","journal-title":"Dig. Liver Dis."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1038\/cr.2016.39","article-title":"Ubiquitin modifications","volume":"26","author":"Swatek","year":"2016","journal-title":"Cell Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"4535","DOI":"10.1128\/MCB.19.6.4535","article-title":"Identification of CHIP, a novel tetratricopeptide repeat-containing protein that interacts with heat shock proteins and negatively regulates chaperone functions","volume":"19","author":"Ballinger","year":"1999","journal-title":"Mol. Cell. Biol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"22267","DOI":"10.1074\/jbc.M700513200","article-title":"Chaperone functions of the E3 ubiquitin ligase CHIP","volume":"282","author":"Rosser","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1016\/S0968-0004(02)02125-4","article-title":"Protein quality control: U-box-containing E3 ubiquitin ligases join the fold","volume":"27","author":"Cyr","year":"2002","journal-title":"Trends Biochem. Sci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.abb.2008.12.001","article-title":"CYP3A4 ubiquitination by gp78 (the tumor autocrine motility factor receptor, AMFR) and CHIP E3 ligases","volume":"483","author":"Pabarcus","year":"2009","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"31177","DOI":"10.1074\/jbc.M113.470500","article-title":"RNF185 is a novel E3 ligase of endoplasmic reticulum-associated degradation (ERAD) that targets cystic fibrosis transmembrane conductance regulator (CFTR)","volume":"288","author":"Toledano","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_31","first-page":"438","article-title":"CHIP, a carboxy terminus HSP-70 interacting protein, prevents cell death induced by endoplasmic reticulum stress in the central nervous system","volume":"8","author":"Hauswirth","year":"2014","journal-title":"Front. Cell. Neurosci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"536","DOI":"10.1161\/CIRCRESAHA.111.254730","article-title":"p90RSK targets the ERK5-CHIP ubiquitin E3 ligase activity in diabetic hearts and promotes cardiac apoptosis and dysfunction","volume":"110","author":"Le","year":"2012","journal-title":"Circ. Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1164\/rccm.201305-0874OC","article-title":"Regulation of IL-4 receptor signaling by STUB1 in lung inflammation","volume":"189","author":"Wei","year":"2014","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"11704","DOI":"10.1074\/jbc.M114.635086","article-title":"Carboxyl terminus of HSC70-interacting protein (CHIP) down-regulates NF-kappaB-inducing kinase (NIK) and suppresses NIK-induced liver injury","volume":"290","author":"Jiang","year":"2015","journal-title":"J. Biol. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"29423","DOI":"10.1038\/srep29423","article-title":"CHIP(\u2212\/\u2212)-Mouse Liver: Adiponectin-AMPK-FOXO-Activation Overrides CYP2E1-Elicited JNK1-Activation, Delaying Onset of NASH: Therapeutic Implications","volume":"6","author":"Kim","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"5446","DOI":"10.1093\/emboj\/cdg529","article-title":"CHIP activates HSF1 and confers protection against apoptosis and cellular stress","volume":"22","author":"Dai","year":"2003","journal-title":"EMBO J."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"4018","DOI":"10.1128\/MCB.00296-08","article-title":"CHIP deficiency decreases longevity, with accelerated aging phenotypes accompanied by altered protein quality control","volume":"28","author":"Min","year":"2008","journal-title":"Mol. Cell. Biol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"100086","DOI":"10.1016\/j.xpro.2020.100086","article-title":"Protocol for Primary Mouse Hepatocyte Isolation","volume":"1","author":"Goldstein","year":"2020","journal-title":"STAR Protoc."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1768","DOI":"10.3748\/wjg.v20.i7.1768","article-title":"Role of endoplasmic reticulum stress in the pathogenesis of nonalcoholic fatty liver disease","volume":"20","author":"Zhang","year":"2014","journal-title":"World J. Gastroenterol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"875","DOI":"10.1007\/s00125-012-2811-y","article-title":"Impaired Akt phosphorylation in insulin-resistant human muscle is accompanied by selective and heterogeneous downstream defects","volume":"56","author":"Tonks","year":"2013","journal-title":"Diabetologia"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1038\/ni.1831","article-title":"Thioredoxin-interacting protein links oxidative stress to inflammasome activation","volume":"11","author":"Zhou","year":"2010","journal-title":"Nat. Immunol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"780496","DOI":"10.3389\/fphar.2022.780496","article-title":"The NLRP3 Inflammasome in Non-Alcoholic Fatty Liver Disease and Steatohepatitis: Therapeutic Targets and Treatment","volume":"13","author":"Yu","year":"2022","journal-title":"Front. Pharm."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1530\/JME-12-0091","article-title":"Posttranslational regulation of thioredoxin-interacting protein","volume":"50","author":"Robinson","year":"2013","journal-title":"J. Mol. Endocrinol."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Alvarez, C.E. (2008). On the origins of arrestin and rhodopsin. BMC Evol. Biol., 8.","DOI":"10.1186\/1471-2148-8-222"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"8869","DOI":"10.1074\/jbc.M109.063321","article-title":"The ubiquitin ligase itch regulates apoptosis by targeting thioredoxin-interacting protein for ubiquitin-dependent degradation","volume":"285","author":"Zhang","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"42938","DOI":"10.1074\/jbc.M101968200","article-title":"CHIP is a U-box-dependent E3 ubiquitin ligase: Identification of Hsc70 as a target for ubiquitylation","volume":"276","author":"Jiang","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"699756","DOI":"10.3389\/fpls.2021.699756","article-title":"Conserved and Unique Roles of Chaperone-Dependent E3 Ubiquitin Ligase CHIP in Plants","volume":"12","author":"Zhang","year":"2021","journal-title":"Front. Plant Sci."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1083\/jcb.201110131","article-title":"The impact of the unfolded protein response on human disease","volume":"197","author":"Wang","year":"2012","journal-title":"J. Cell Biol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1492","DOI":"10.1126\/science.1158042","article-title":"Regulation of hepatic lipogenesis by the transcription factor XBP1","volume":"320","author":"Lee","year":"2008","journal-title":"Science"},{"key":"ref_50","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_51","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_52","doi-asserted-by":"crossref","first-page":"520","DOI":"10.1016\/j.cmet.2008.04.011","article-title":"Dephosphorylation of translation initiation factor 2alpha enhances glucose tolerance and attenuates hepatosteatosis in mice","volume":"7","author":"Oyadomari","year":"2008","journal-title":"Cell Metab."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1016\/0021-9150(93)90209-D","article-title":"Effects of a high-fat, sucrose diet on serum insulin and related atherosclerotic risk factors in rats","volume":"100","author":"Barnard","year":"1993","journal-title":"Atherosclerosis"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1203\/00006450-199407001-00017","article-title":"The effect of excess dietary sucrose on growth, blood pressure, and metabolism in developing Sprague-Dawley rats","volume":"36","author":"Hulman","year":"1994","journal-title":"Pediatr. Res."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1323","DOI":"10.1161\/01.HYP.37.5.1323","article-title":"Reversibility of chronic experimental syndrome X by diet modification","volume":"37","author":"Roberts","year":"2001","journal-title":"Hypertension"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1186\/1758-5996-4-32","article-title":"Diet high in fat and sucrose induces rapid onset of obesity-related metabolic syndrome partly through rapid response of genes involved in lipogenesis, insulin signalling and inflammation in mice","volume":"4","author":"Yang","year":"2012","journal-title":"Diabetol. Metab. Syndr."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1632","DOI":"10.1002\/hep.26594","article-title":"High-fat and high-sucrose (western) diet induces steatohepatitis that is dependent on fructokinase","volume":"58","author":"Ishimoto","year":"2013","journal-title":"Hepatology"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1007\/s00535-013-0758-5","article-title":"Mechanisms of hepatic triglyceride accumulation in non-alcoholic fatty liver disease","volume":"48","author":"Kawano","year":"2013","journal-title":"J. Gastroenterol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1016\/j.jcmgh.2020.07.006","article-title":"Impaired Hepatic Vitamin A Metabolism in NAFLD Mice Leading to Vitamin A Accumulation in Hepatocytes","volume":"11","author":"Saeed","year":"2021","journal-title":"Cell. Mol. Gastroenterol. Hepatol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1002\/jcp.25921","article-title":"All-trans retinoic acid ameliorates hepatic stellate cell activation via suppression of thioredoxin interacting protein expression","volume":"233","author":"Shimizu","year":"2018","journal-title":"J. Cell. Physiol."}],"container-title":["Antioxidants"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3921\/12\/2\/458\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:31:17Z","timestamp":1760121077000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3921\/12\/2\/458"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2,11]]},"references-count":60,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2023,2]]}},"alternative-id":["antiox12020458"],"URL":"https:\/\/doi.org\/10.3390\/antiox12020458","relation":{},"ISSN":["2076-3921"],"issn-type":[{"type":"electronic","value":"2076-3921"}],"subject":[],"published":{"date-parts":[[2023,2,11]]}}}