{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T16:07:15Z","timestamp":1790611635563,"version":"4.1.0"},"reference-count":37,"publisher":"Public Library of Science (PLoS)","issue":"12","license":[{"start":{"date-parts":[[2019,12,5]],"date-time":"2019-12-05T00:00:00Z","timestamp":1575504000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["RO1HL-137004"],"award-info":[{"award-number":["RO1HL-137004"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Ohio Department of Higher Education"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"DOI":"10.1371\/journal.pone.0225604","type":"journal-article","created":{"date-parts":[[2019,12,5]],"date-time":"2019-12-05T13:47:32Z","timestamp":1575553652000},"page":"e0225604","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":26,"title":["Hyperglycemia induces key genetic and phenotypic changes in human liver epithelial HepG2 cells which parallel the Leprdb\/J mouse model of non-alcoholic fatty liver disease (NAFLD)"],"prefix":"10.1371","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7423-0939","authenticated-orcid":true,"given":"Robin C.","family":"Su","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Apurva","family":"Lad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5892-1879","authenticated-orcid":true,"given":"Joshua D.","family":"Breidenbach","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas M.","family":"Blomquist","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William T.","family":"Gunning","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Prabhatchandra","family":"Dube","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew L.","family":"Kleinhenz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deepak","family":"Malhotra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven T.","family":"Haller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David J.","family":"Kennedy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2019,12,5]]},"reference":[{"issue":"4","key":"pone.0225604.ref001","doi-asserted-by":"crossref","first-page":"1134","DOI":"10.1053\/j.gastro.2009.02.038","article-title":"Burden of digestive diseases in the United States Part III: Liver, biliary tract, and pancreas","volume":"136","author":"JE Everhart","year":"2009","journal-title":"Gastroenterology"},{"issue":"5","key":"pone.0225604.ref002","doi-asserted-by":"crossref","first-page":"707","DOI":"10.5604\/01.3001.0010.2713","article-title":"Models of non-Alcoholic Fatty Liver Disease and Potential Translational Value: the Effects of 3,5-L-diiodothyronine","volume":"16","author":"E Grasselli","year":"2017","journal-title":"Ann Hepatol"},{"issue":"1","key":"pone.0225604.ref003","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1002\/hep.28431","article-title":"Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes","volume":"64","author":"ZM Younossi","year":"2016","journal-title":"Hepatology"},{"issue":"9","key":"pone.0225604.ref004","doi-asserted-by":"crossref","DOI":"10.3390\/ijms19092566","article-title":"Telocinobufagin, a Novel Cardiotonic Steroid, Promotes Renal Fibrosis via Na(+)\/K(+)-ATPase Profibrotic Signaling Pathways","volume":"19","author":"DJ Kennedy","year":"2018","journal-title":"Int J Mol Sci"},{"issue":"2","key":"pone.0225604.ref005","first-page":"26 1","article-title":"Quantification of Lactate Dehydrogenase for Cell Viability Testing Using Cell Lines and Primary Cultured Astrocytes","volume":"72","author":"S Kaja","year":"2017","journal-title":"Curr Protoc Toxicol"},{"issue":"1\u20132","key":"pone.0225604.ref006","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/0022-1759(83)90303-4","article-title":"Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays","volume":"65","author":"T Mosmann","year":"1983","journal-title":"J Immunol Methods"},{"issue":"43","key":"pone.0225604.ref007","doi-asserted-by":"crossref","first-page":"9488","DOI":"10.3748\/wjg.v22.i43.9488","article-title":"Nonalcoholic fatty liver disease\u2014A multisystem disease?","volume":"22","author":"I Mikolasevic","year":"2016","journal-title":"World J Gastroenterol"},{"issue":"Suppl1","key":"pone.0225604.ref008","first-page":"S1","article-title":"Type 2 diabetes mellitus and non-alcoholic fatty liver disease: a systematic review and meta-analysis","volume":"10","author":"N Amiri Dash Atan","year":"2017","journal-title":"Gastroenterol Hepatol Bed Bench"},{"issue":"42","key":"pone.0225604.ref009","doi-asserted-by":"crossref","first-page":"5286","DOI":"10.3748\/wjg.v16.i42.5286","article-title":"Histopathology of nonalcoholic fatty liver disease","volume":"16","author":"EM Brunt","year":"2010","journal-title":"World J Gastroenterol"},{"issue":"6","key":"pone.0225604.ref010","doi-asserted-by":"crossref","first-page":"3077","DOI":"10.1073\/pnas.0630588100","article-title":"Triglyceride accumulation protects against fatty acid-induced lipotoxicity","volume":"100","author":"LL Listenberger","year":"2003","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"3","key":"pone.0225604.ref011","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1503\/cmaj.1040752","article-title":"Liver enzyme alteration: a guide for clinicians","volume":"172","author":"EG Giannini","year":"2005","journal-title":"CMAJ"},{"issue":"11","key":"pone.0225604.ref012","first-page":"709","article-title":"Mildly Elevated Liver Transaminase Levels","volume":"96","author":"RC Oh","year":"2017","journal-title":"Causes and Evaluation. Am Fam Physician"},{"issue":"2","key":"pone.0225604.ref013","doi-asserted-by":"crossref","first-page":"570","DOI":"10.1210\/en.2015-1866","article-title":"Hepatocyte-Specific Disruption of CD36 Attenuates Fatty Liver and Improves Insulin Sensitivity in HFD-Fed Mice","volume":"157","author":"CG Wilson","year":"2016","journal-title":"Endocrinology"},{"issue":"1","key":"pone.0225604.ref014","doi-asserted-by":"crossref","first-page":"387","DOI":"10.3892\/mmr.2016.6025","article-title":"Involvement of xanthine oxidase and paraoxonase 1 in the process of oxidative stress in nonalcoholic fatty liver disease","volume":"15","author":"B Wang","year":"2017","journal-title":"Mol Med Rep"},{"issue":"12","key":"pone.0225604.ref015","first-page":"719","article-title":"Paraoxonase activity in sera of patients with non-alcoholic fatty liver disease","volume":"118","author":"M Fedelesova","year":"2017","journal-title":"Bratisl Lek Listy"},{"issue":"4","key":"pone.0225604.ref016","doi-asserted-by":"crossref","first-page":"1946","DOI":"10.1021\/pr400050u","article-title":"Paraoxonase-1 deficiency is associated with severe liver steatosis in mice fed a high-fat high-cholesterol diet: a metabolomic approach","volume":"12","author":"A Garcia-Heredia","year":"2013","journal-title":"J Proteome Res"},{"key":"pone.0225604.ref017","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1186\/s12014-018-9186-0","article-title":"Proteomic characterization of high-density lipoprotein particles in patients with non-alcoholic fatty liver disease","volume":"15","author":"PK Rao","year":"2018","journal-title":"Clin Proteomics"},{"key":"pone.0225604.ref018","doi-asserted-by":"crossref","first-page":"265305","DOI":"10.1155\/2012\/265305","article-title":"Paraoxonase activity and expression is modulated by therapeutics in experimental rat nonalcoholic Fatty liver disease","volume":"2012","author":"O Hussein","year":"2012","journal-title":"Int J Hepatol"},{"issue":"8","key":"pone.0225604.ref019","doi-asserted-by":"crossref","first-page":"2780","DOI":"10.2337\/db14-1772","article-title":"Forced Hepatic Overexpression of CEACAM1 Curtails Diet-Induced Insulin Resistance","volume":"64","author":"QY Al-Share","year":"2015","journal-title":"Diabetes"},{"issue":"7","key":"pone.0225604.ref020","doi-asserted-by":"crossref","first-page":"3225","DOI":"10.1210\/en.2009-1158","article-title":"Susceptibility to diet-induced hepatic steatosis and glucocorticoid resistance in FK506-binding protein 52-deficient mice","volume":"151","author":"M Warrier","year":"2010","journal-title":"Endocrinology"},{"key":"pone.0225604.ref021","doi-asserted-by":"crossref","first-page":"8","DOI":"10.3389\/fendo.2017.00008","article-title":"Loss of Hepatic CEACAM1: A Unifying Mechanism Linking Insulin Resistance to Obesity and Non-Alcoholic Fatty Liver Disease","volume":"8","author":"G Heinrich","year":"2017","journal-title":"Front Endocrinol (Lausanne)"},{"issue":"8","key":"pone.0225604.ref022","doi-asserted-by":"crossref","first-page":"2199","DOI":"10.2337\/db07-1087","article-title":"Pck1 gene silencing in the liver improves glycemia control, insulin sensitivity, and dyslipidemia in db\/db mice","volume":"57","author":"AG Gomez-Valades","year":"2008","journal-title":"Diabetes"},{"issue":"12","key":"pone.0225604.ref023","doi-asserted-by":"crossref","first-page":"4636","DOI":"10.1210\/en.2002-220732","article-title":"Mechanisms by which bis(maltolato)oxovanadium(IV) normalizes phosphoenolpyruvate carboxykinase and glucose-6-phosphatase expression in streptozotocin-diabetic rats in vivo","volume":"143","author":"L Marzban","year":"2002","journal-title":"Endocrinology"},{"issue":"3","key":"pone.0225604.ref024","doi-asserted-by":"crossref","first-page":"e57766","DOI":"10.1371\/journal.pone.0057766","article-title":"Gene expression profile analysis of type 2 diabetic mouse liver","volume":"8","author":"F Zhang","year":"2013","journal-title":"PLoS One"},{"issue":"3","key":"pone.0225604.ref025","doi-asserted-by":"crossref","first-page":"767","DOI":"10.3892\/ijmm.2015.2270","article-title":"Treatment with PPARdelta agonist alleviates non-alcoholic fatty liver disease by modulating glucose and fatty acid metabolic enzymes in a rat model","volume":"36","author":"X Li","year":"2015","journal-title":"Int J Mol Med"},{"issue":"1","key":"pone.0225604.ref026","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1002\/path.4829","article-title":"Animal models of non-alcoholic fatty liver disease: current perspectives and recent advances","volume":"241","author":"JK Lau","year":"2017","journal-title":"J Pathol"},{"issue":"1","key":"pone.0225604.ref027","doi-asserted-by":"crossref","first-page":"e283","DOI":"10.1038\/emm.2016.123","article-title":"Gene-metabolite network analysis in different nonalcoholic fatty liver disease phenotypes","volume":"49","author":"XL Liu","year":"2017","journal-title":"Exp Mol Med"},{"key":"pone.0225604.ref028","doi-asserted-by":"crossref","first-page":"46658","DOI":"10.1038\/srep46658","article-title":"Metabolism dysregulation induces a specific lipid signature of nonalcoholic steatohepatitis in patients","volume":"7","author":"F Chiappini","year":"2017","journal-title":"Sci Rep"},{"issue":"4","key":"pone.0225604.ref029","first-page":"507","article-title":"SREBP-1c, regulated by the insulin and AMPK signaling pathways, plays a role in nonalcoholic fatty liver disease","volume":"21","author":"M Kohjima","year":"2008","journal-title":"Int J Mol Med"},{"issue":"2","key":"pone.0225604.ref030","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1002\/hep.26272","article-title":"Thyroid hormone-responsive SPOT 14 homolog promotes hepatic lipogenesis, and its expression is regulated by liver X receptor alpha through a sterol regulatory element-binding protein 1c-dependent mechanism in mice","volume":"58","author":"J Wu","year":"2013","journal-title":"Hepatology"},{"issue":"10","key":"pone.0225604.ref031","doi-asserted-by":"crossref","first-page":"2087","DOI":"10.1124\/dmd.109.027466","article-title":"Hepatic cytochrome P450 enzyme alterations in humans with progressive stages of nonalcoholic fatty liver disease","volume":"37","author":"CD Fisher","year":"2009","journal-title":"Drug Metab Dispos"},{"issue":"10","key":"pone.0225604.ref032","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1016\/j.jnutbio.2008.07.005","article-title":"Polymorphisms of MRP2 (ABCC2) are associated with susceptibility to nonalcoholic fatty liver disease","volume":"20","author":"S Sookoian","year":"2009","journal-title":"J Nutr Biochem"},{"issue":"4","key":"pone.0225604.ref033","doi-asserted-by":"crossref","first-page":"588","DOI":"10.1002\/ptr.3305","article-title":"Reduction of lipid accumulation in HepG2 cells by luteolin is associated with activation of AMPK and mitigation of oxidative stress","volume":"25","author":"JF Liu","year":"2011","journal-title":"Phytother Res"},{"issue":"5","key":"pone.0225604.ref034","article-title":"Palmitic acid induced lipotoxicity is associated with altered lipid metabolism, enhanced CYP450 2E1 and intracellular calcium mediated ER stress in human hepatoma cells","author":"U Ashraf","year":"2015","journal-title":"Toxicology Research"},{"issue":"1","key":"pone.0225604.ref035","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1007\/s11596-012-0009-7","article-title":"Reduction of insulin resistance in HepG2 cells by knockdown of LITAF expression in human THP-1 macrophages","volume":"32","author":"Y Huang","year":"2012","journal-title":"J Huazhong Univ Sci Technolog Med Sci"},{"issue":"6","key":"pone.0225604.ref036","doi-asserted-by":"crossref","first-page":"3216","DOI":"10.1074\/jbc.272.6.3216","article-title":"Dexamethasone induces posttranslational degradation of GLUT2 and inhibition of insulin secretion in isolated pancreatic beta cells. Comparison with the effects of fatty acids","volume":"272","author":"S Gremlich","year":"1997","journal-title":"J Biol Chem"},{"issue":"8","key":"pone.0225604.ref037","doi-asserted-by":"crossref","first-page":"1581","DOI":"10.1016\/j.tiv.2007.05.014","article-title":"Cytochrome P450 enzyme levels in HepG2 cells and cryopreserved primary human hepatocytes and their induction in HepG2 cells","volume":"21","author":"WM Westerink","year":"2007","journal-title":"Toxicol In Vitro"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0225604","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2019,12,5]],"date-time":"2019-12-05T13:48:07Z","timestamp":1575553687000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0225604"}},"subtitle":[],"editor":[{"given":"Luca","family":"Vanella","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2019,12,5]]},"references-count":37,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2019,12,5]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0225604","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,12,5]]}}}