{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,5]],"date-time":"2026-09-05T23:13:24Z","timestamp":1788650004273,"version":"build-2803163510"},"reference-count":78,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2025,12,17]],"date-time":"2025-12-17T00:00:00Z","timestamp":1765929600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"name":"Agence National de la Recherche","award":["ANR-23-CE18-0035-0"],"award-info":[{"award-number":["ANR-23-CE18-0035-0"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,2,18]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Metabolic dysfunction-associated steatotic liver disease (MASLD) is one of the most prevalent liver disorders, affecting approximately one-third of the global adult population. The disease begins with hepatic fat accumulation (steatosis) and can progress to inflammation, fibrosis, and hepatocellular carcinoma. To elucidate the complex mechanisms underlying MASLD, we have developed a novel mathematical model that integrates glucose and lipid metabolisms, oxidative stress, insulin signaling and insulin resistance, and cytokines functions. We demonstrated that variations in extracellular fatty acid and lactate levels, along with changes in the activities of key glycolytic and triglyceride-synthesizing enzymes observed in actual patients, exert a substantial impact on oxidative stress and subsequent cellular damage. Moreover, this model enabled us to evaluate daily metabolic dynamics associated with protein expression patterns specific to steatotic livers. Importantly, it also allowed simulation of cytokine release from hepatocytes into the bloodstream (autocrine and endocrine effects) and the impact of locally elevated cytokines concentrations derived from immune cells (paracrine effects). Our model revealed the dynamics of the early stages of MASLD progression in response to alterations in blood metabolite levels, hepatic enzyme activities, insulin profiles, and cytokine patterns. Furthermore, we identified specific combinations of these factors that may mitigate hepatic fat accumulation or oxidative stress, highlighting the importance of patient-specificity. This study presents the first mechanistic framework grounded in experimental data to describe the crosstalk among hepatic metabolism, insulin, and cytokines, serving as a powerful tool for elucidating disease mechanisms and developing therapeutic strategies.<\/jats:p>","DOI":"10.1093\/toxsci\/kfaf176","type":"journal-article","created":{"date-parts":[[2025,12,17]],"date-time":"2025-12-17T16:21:02Z","timestamp":1765988462000},"source":"Crossref","is-referenced-by-count":2,"title":["A computational model of inflammation reveals crosstalk among energy metabolism, oxidative stress, insulin, and cytokines in hepatocytes during early MASLD progression"],"prefix":"10.1093","volume":"209","author":[{"given":"Yuki","family":"Miura","sequence":"first","affiliation":[{"name":"Department of Chemical System Engineering, Graduate school of Engineering, The University of Tokyo , Tokyo 113-8656,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2249-6516","authenticated-orcid":false,"given":"Yasuyuki","family":"Sakai","sequence":"additional","affiliation":[{"name":"Department of Chemical System Engineering, Graduate school of Engineering, The University of Tokyo , Tokyo 113-8656,","place":["Japan"]},{"name":"CNRS IRL 2820, Laboratory for Integrated Micro Mechatronic Systems, Institute of Industrial Science, University of Tokyo , Tokyo 153-8505,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4253-3211","authenticated-orcid":false,"given":"Masaki","family":"Nishikawa","sequence":"additional","affiliation":[{"name":"Department of Chemical System Engineering, Graduate school of Engineering, The University of Tokyo , Tokyo 113-8656,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Leclerc","sequence":"additional","affiliation":[{"name":"CNRS IRL 2820, Laboratory for Integrated Micro Mechatronic Systems, Institute of Industrial Science, University of Tokyo , Tokyo 153-8505,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,12,17]]},"reference":[{"key":"2026022209371723700_kfaf176-B1","doi-asserted-by":"publisher","first-page":"1452","DOI":"10.1007\/s00125-004-1465-9","article-title":"Chronic hyperglycaemia promotes lipogenesis and triacylglycerol accumulation in human skeletal muscle cells","volume":"47","author":"Aas","year":"2004","journal-title":"Diabetologia"},{"key":"2026022209371723700_kfaf176-B3","doi-asserted-by":"publisher","first-page":"4189","DOI":"10.3390\/ijms21114189","article-title":"Relationship between IL-8 circulating levels and TLR2 hepatic expression in women with morbid obesity and nonalcoholic steatohepatitis","volume":"21","author":"Auguet","year":"2020","journal-title":"Int J Mol Sci"},{"key":"2026022209371723700_kfaf176-B4","doi-asserted-by":"publisher","first-page":"866","DOI":"10.2337\/dc08-1826","article-title":"Effects of type 2 diabetes on insulin secretion, insulin action, glucose effectiveness, and postprandial glucose metabolism","volume":"32","author":"Basu","year":"2009","journal-title":"Diabetes Care"},{"key":"2026022209371723700_kfaf176-B5","doi-asserted-by":"publisher","first-page":"2386","DOI":"10.1038\/s41467-018-04720-9","article-title":"HEPATOKIN1 is a biochemistry-based model of liver metabolism for applications in medicine and pharmacology","volume":"9","author":"Berndt","year":"2018","journal-title":"Nat Commun"},{"key":"2026022209371723700_kfaf176-B6","doi-asserted-by":"publisher","first-page":"352","DOI":"10.1038\/s41423-021-00782-w","article-title":"Supplying the trip to antibody production-nutrients, signaling, and the programming of cellular metabolism in the mature B lineage","volume":"19","author":"Boothby","year":"2022","journal-title":"Cell Mol Immunol"},{"key":"2026022209371723700_kfaf176-B7","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1042\/bj3010193","article-title":"Interleukin-6, but not tumour necrosis factor-alpha, increases lipogenesis in rat hepatocyte primary cultures","volume":"301(Pt 1)","author":"Brass","year":"1994","journal-title":"Biochem J"},{"issue":":","key":"2026022209371723700_kfaf176-B07649477","doi-asserted-by":"publisher","first-page":"2178","DOI":"10.1002\/hep.26988","article-title":"Relationship between disease severity, hyperinsulinemia, and impaired insulin clearance in patients with nonalcoholic steatohepatitis","volume":"59","author":"Bril","year":"2014","journal-title":"Hepatology"},{"key":"2026022209371723700_kfaf176-B8","doi-asserted-by":"publisher","first-page":"1291","DOI":"10.1016\/j.cmet.2019.03.014","article-title":"Pyruvate-carboxylase-mediated anaplerosis promotes antioxidant capacity by sustaining TCA cycle and redox metabolism in liver","volume":"29","author":"Cappel","year":"2019","journal-title":"Cell Metab"},{"issue":":","key":"2026022209371723700_kfaf176-B2067991","doi-asserted-by":"publisher","first-page":"115006","DOI":"10.1016\/j.celrep.2024.115006","article-title":"Carnitine palmitoyltransferase 1 facilitates fatty acid oxidation in a non-cell-autonomous manner","volume":"43","author":"Choi","year":"2024","journal-title":"Cell Reports"},{"key":"2026022209371723700_kfaf176-B11","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1111\/acel.12305","article-title":"Age-related sensitivity to endotoxin-induced liver inflammation: implication of inflammasome\/IL-1\u03b2 for steatohepatitis","volume":"14","author":"Chung","year":"2015","journal-title":"Aging Cell"},{"key":"2026022209371723700_kfaf176-B13","doi-asserted-by":"publisher","first-page":"3935","DOI":"10.1016\/j.csbj.2022.07.034","article-title":"A combined metabolomics and molecular biology approach to reveal hepatic injury and underlying mechanisms after chronic l-lactate exposure in mice","volume":"20","author":"Dong","year":"2022","journal-title":"Comput Struct Biotechnol J"},{"key":"2026022209371723700_kfaf176-B14","doi-asserted-by":"publisher","first-page":"880298","DOI":"10.3389\/fimmu.2022.880298","article-title":"Association of inflammatory cytokines with non-alcoholic fatty liver disease","volume":"13","author":"Duan","year":"2022","journal-title":"Front Immunol"},{"issue":":","key":"2026022209371723700_kfaf176-B5442474","doi-asserted-by":"publisher","first-page":"424","DOI":"10.1053\/j.gastro.2007.11.038","article-title":"Alterations in adipose tissue and hepatic lipid kinetics in obese men and women with nonalcoholic fatty liver disease","volume":"134","author":"Fabbrini","year":"2008","journal-title":"Gastroenterology"},{"key":"2026022209371723700_kfaf176-B16","doi-asserted-by":"publisher","first-page":"e00066","DOI":"10.1097\/IN9.0000000000000066","article-title":"Metabolic diseases and Kupffer cell\u2019s plasticity","volume":"7","author":"Fantini","year":"2025","journal-title":"Immunometabolism (Cobham)"},{"issue":":","key":"2026022209371723700_kfaf176-B6565522","doi-asserted-by":"publisher","first-page":"479","DOI":"10.3390\/ijms17040479","article-title":"Different serum free fatty acid profiles in NAFLD subjects and healthy controls after oral fat load","volume":"17","author":"Gambino","year":"2016","journal-title":"IJMS"},{"key":"2026022209371723700_kfaf176-B18","doi-asserted-by":"publisher","first-page":"457","DOI":"10.1214\/ss\/1177011136","article-title":"Inference from iterative simulation using multiple sequences","volume":"7","author":"Gelman","year":"1992","journal-title":"Statist Sci"},{"key":"2026022209371723700_kfaf176-B19","doi-asserted-by":"publisher","first-page":"2008","DOI":"10.3390\/nu11092008","article-title":"Palm oil on the edge","volume":"11","author":"Gesteiro","year":"2019","journal-title":"Nutrients"},{"issue":":","key":"2026022209371723700_kfaf176-B26189187","doi-asserted-by":"publisher","first-page":"572","DOI":"10.1038\/s42255-023-00775-1","article-title":"A proteo-transcriptomic map of non-alcoholic fatty liver disease signatures","volume":"5","author":"Govaere","year":"2023","journal-title":"Nat Metab"},{"key":"2026022209371723700_kfaf176-B20","doi-asserted-by":"crossref","first-page":"7558","DOI":"10.1016\/S0021-9258(18)35980-5","article-title":"Potent and specific inhibition of glutathione synthesis by buthionine sulfoximine (S-n-butyl homocysteine sulfoximine)","volume":"254","author":"Griffith","year":"1979","journal-title":"J Biol Chem"},{"key":"2026022209371723700_kfaf176-B21","doi-asserted-by":"publisher","first-page":"92791","DOI":"10.4291\/wjgp.v15.i2.92791","article-title":"Metabolic dysfunction-associated steatotic liver disease heterogeneity: need of subtyping","volume":"15","author":"Habib","year":"2024","journal-title":"World J Gastrointest Pathophysiol"},{"key":"2026022209371723700_kfaf176-B22","doi-asserted-by":"publisher","first-page":"2293","DOI":"10.1124\/dmd.110.035006","article-title":"Diversity in antioxidant response enzymes in progressive stages of human nonalcoholic fatty liver disease","volume":"38","author":"Hardwick","year":"2010","journal-title":"Drug Metab Dispos"},{"issue":":","key":"2026022209371723700_kfaf176-B98264007","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1016\/s1388-1981(99)00138-9","article-title":"Inactivation of microsomal triglyceride transfer protein impairs the normal redistribution but not the turnover of newly synthesized glycerolipid in the cytosol, endoplasmic reticulum and golgi of primary rat hepatocytes","volume":"1441","author":"Hebbachi","year":"1999","journal-title":"Biochim Biophys Acta"},{"key":"2026022209371723700_kfaf176-B24","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1016\/s0741-8329","article-title":"Ethanol, oxidative stress, and cytokine-induced liver cell injury","volume":"27","author":"Hoek","year":"2002","journal-title":"Alcohol"},{"key":"2026022209371723700_kfaf176-B26","doi-asserted-by":"publisher","first-page":"e0286416","DOI":"10.1371\/journal.pone.0286416","article-title":"A plausible identifiable model of the canonical NF-\u03baB signaling pathway","volume":"18","author":"Jaruszewicz-B\u0142o\u0144ska","year":"2023","journal-title":"PLoS One"},{"issue":"514","key":"2026022209371723700_kfaf176-B6381053","doi-asserted-by":"publisher","DOI":"10.1038\/s42003-020-01231-6","article-title":"A dietary anthocyanin cyanidin-3-O-glucoside binds to ppars to regulate glucose metabolism and insulin sensitivity in mice","volume":"3","author":"Jia","year":"2020","journal-title":"Commun Biol"},{"key":"2026022209371723700_kfaf176-B27","first-page":"1304","article-title":"Cytokine gene expression by Kupffer cells in experimental alcoholic liver disease","volume":"22","author":"Kamimura","year":"1995","journal-title":"Hepatol. Baltim. Md"},{"key":"2026022209371723700_kfaf176-B7050128","doi-asserted-by":"publisher","first-page":"101315","DOI":"10.1016\/j.redox.2019.101315","article-title":"Peroxiredoxin 5 ameliorates obesity-induced non-alcoholic fatty liver disease through the regulation of oxidative stress and AMP-activated protein kinase signaling","volume":"28","author":"Kim","year":"2020","journal-title":"Redox Biol"},{"issue":":","key":"2026022209371723700_kfaf176-B0097595","doi-asserted-by":"publisher","first-page":"e12788","DOI":"10.14814\/phy2.12788","article-title":"Skeletal muscle IL-6 AND regulation of liver metabolism during high-fat diet and exercise training","volume":"4","author":"Knudsen","year":"2016","journal-title":"Physiol Rep"},{"key":"2026022209371723700_kfaf176-B29","first-page":"351","article-title":"Re-evaluation of fatty acid metabolism-related gene expression in nonalcoholic fatty liver disease","volume":"20","author":"Kohjima","year":"2007","journal-title":"Int J Mol Med"},{"key":"2026022209371723700_kfaf176-B30","doi-asserted-by":"publisher","first-page":"21327","DOI":"10.1074\/jbc.M701759200","article-title":"Mitochondrial reactive oxygen species signal hepatocyte steatosis by regulating the phosphatidylinositol 3-kinase cell survival pathway","volume":"282","author":"Kohli","year":"2007","journal-title":"J Biol Chem"},{"key":"2026022209371723700_kfaf176-B31","doi-asserted-by":"publisher","first-page":"e1002577","DOI":"10.1371\/journal.pcbi.1002577","article-title":"Quantifying the contribution of the liver to glucose homeostasis: a detailed kinetic model of human hepatic glucose metabolism","volume":"8","author":"K\u00f6nig","year":"2012","journal-title":"PLoS Comput Biol"},{"key":"2026022209371723700_kfaf176-B32","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.bbamem.2015.10.004","article-title":"Mammalian aquaglyceroporin function in metabolism","volume":"1858","author":"Laforenza","year":"2016","journal-title":"Biochim Biophys Acta"},{"issue":":","key":"2026022209371723700_kfaf176-B2959715","doi-asserted-by":"publisher","first-page":"2350","DOI":"10.1126\/science.289.5488.2350","article-title":"Failure to regulate TNF-induced NF-\u03bab and cell death responses in A20-deficient mice","volume":"289","author":"Lee","year":"2000","journal-title":"Science"},{"key":"2026022209371723700_kfaf176-B33","doi-asserted-by":"publisher","first-page":"7","DOI":"10.5493\/wjem.v13.i3.7","article-title":"Physiopathological mechanisms related to inflammation in obesity and type 2 diabetes mellitus","volume":"13","author":"Lempesis","year":"2023","journal-title":"World J Exp Med"},{"key":"2026022209371723700_kfaf176-B34","doi-asserted-by":"publisher","first-page":"4778","DOI":"10.3748\/wjg.v20.i16.4778","article-title":"Proteomic analysis of liver mitochondria from rats with nonalcoholic steatohepatitis","volume":"20","author":"Li","year":"2014","journal-title":"World J Gastroenterol"},{"key":"2026022209371723700_kfaf176-B37","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1016\/j.mbs.2009.07.005","article-title":"A molecular mathematical model of glucose mobilization and uptake","volume":"221","author":"Liu","year":"2009","journal-title":"Math Biosci"},{"key":"2026022209371723700_kfaf176-B2477871","first-page":"10","author":"Lodish","journal-title":"Molecular cell biology"},{"issue":":","key":"2026022209371723700_kfaf176-B4176931","doi-asserted-by":"publisher","first-page":"9074","DOI":"10.3390\/ijms25169074","article-title":"DGAT1 AND DGAT2 inhibitors for metabolic dysfunction-associated steatotic liver disease (MASLD) management: Benefits for their single or combined application","volume":"25","author":"Longo","year":"2024","journal-title":"IJMS"},{"key":"2026022209371723700_kfaf176-B38","doi-asserted-by":"publisher","first-page":"710420","DOI":"10.3389\/fphys.2021.710420","article-title":"Metabolic changes of hepatocytes in NAFLD","volume":"12","author":"Lu","year":"2021","journal-title":"Front Physiol"},{"key":"2026022209371723700_kfaf176-B39","doi-asserted-by":"crossref","DOI":"10.1186\/1743-7075-9-34","article-title":"Docosahexaenoic acid ameliorates palmitate-induced lipid accumulation and inflammation through repressing NLRC4 inflammasome activation in HepG2 cells","author":"Luo","year":"2012","journal-title":"Nutr M"},{"key":"2026022209371723700_kfaf176-B41","doi-asserted-by":"publisher","first-page":"1133991","DOI":"10.3389\/fendo.2023.1133991","article-title":"Blood lactate levels are associated with an increased risk of metabolic dysfunction-associated fatty liver disease in type 2 diabetes: a real-world study","volume":"14","author":"Ma","year":"2023","journal-title":"Front Endocrinol (Lausanne)"},{"key":"2026022209371723700_kfaf176-B42","doi-asserted-by":"publisher","first-page":"2313","DOI":"10.3390\/ijms24032313","article-title":"Overview of cellular and soluble mediators in systemic inflammation associated with non-alcoholic fatty liver disease","volume":"24","author":"Marques","year":"2023","journal-title":"Int J Mol Sci"},{"key":"2026022209371723700_kfaf176-B44","doi-asserted-by":"publisher","first-page":"117185","DOI":"10.1016\/j.taap.2024.117185","article-title":"A computational model of the crosstalk between hepatocyte fatty acid metabolism and oxidative stress highlights the key enzymes, metabolites, and detoxification pathways in the context of MASLD","volume":"495","author":"Miura","year":"2025","journal-title":"Toxicol Appl Pharmacol"},{"key":"2026022209371723700_kfaf176-B45","doi-asserted-by":"publisher","first-page":"590","DOI":"10.1111\/liv.14309","article-title":"Dietary fatty acid oxidation is decreased in non-alcoholic fatty liver disease: a palmitate breath test study","volume":"40","author":"Naguib","year":"2020","journal-title":"Liver Int"},{"issue":":e8793.","key":"2026022209371723700_kfaf176-B3325781","doi-asserted-by":"publisher","DOI":"10.15252\/msb.20188793","article-title":"Plasma proteome profiling discovers novel proteins associated with non-alcoholic fatty liver disease","volume":"15","author":"Niu","year":"2019","journal-title":"Mol Syst Biol"},{"key":"2026022209371723700_kfaf176-B46","doi-asserted-by":"publisher","first-page":"6289","DOI":"10.1038\/s41598-018-24676-6","article-title":"The CPT1a inhibitor, etomoxir induces severe oxidative stress at commonly used concentrations","volume":"8","author":"O\u2019Connor","year":"2018","journal-title":"Sci Rep"},{"issue":":46.","key":"2026022209371723700_kfaf176-B3754870","doi-asserted-by":"publisher","DOI":"10.1186\/s13036-017-0081-4","article-title":"Bioengineering considerations in liver regenerative medicine","volume":"11","author":"Ogoke","year":"2017","journal-title":"J Biol Eng"},{"issue":":","key":"2026022209371723700_kfaf176-B44456062","doi-asserted-by":"publisher","first-page":"1770","DOI":"10.1111\/liv.14452","article-title":"Cell-type-resolved proteomic analysis of the human liver","volume":"40","author":"\u00d6lander","year":"2020","journal-title":"Liver Int"},{"key":"2026022209371723700_kfaf176-B47","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1038\/s41540-018-0058-z","article-title":"Model-based identification of TNF\u03b1-induced IKK\u03b2-mediated and I\u03baB\u03b1-mediated regulation of NF\u03baB signal transduction as a tool to quantify the impact of drug-induced liver injury compounds","volume":"4","author":"Oppelt","year":"2018","journal-title":"NPJ Syst Biol Appl"},{"key":"2026022209371723700_kfaf176-B48","author":"Optuna","year":"."},{"key":"2026022209371723700_kfaf176-B49","doi-asserted-by":"publisher","first-page":"1385","DOI":"10.1016\/j.freeradbiomed.2013.10.001","article-title":"A biophysically based mathematical model for the catalytic mechanism of glutathione reductase","volume":"65","author":"Pannala","year":"2013","journal-title":"Free Radic Biol Med"},{"key":"2026022209371723700_kfaf176-B50","doi-asserted-by":"publisher","first-page":"1147414","DOI":"10.3389\/fphar.2023.1147414","article-title":"Research progress of glutathione peroxidase family (GPX) in redoxidation","volume":"14","author":"Pei","year":"2023","journal-title":"Front Pharmacol"},{"key":"2026022209371723700_kfaf176-B51","doi-asserted-by":"publisher","first-page":"G1120","DOI":"10.1152\/ajpgi.00407.2007","article-title":"Tumor necrosis factor-alpha directly stimulates the overproduction of hepatic apolipoprotein B100-containing VLDL via impairment of hepatic insulin signaling","volume":"294","author":"Qin","year":"2008","journal-title":"Am J Physiol Gastrointest Liver Physiol"},{"key":"2026022209371723700_kfaf176-B52","doi-asserted-by":"publisher","first-page":"3540","DOI":"10.3748\/wjg.v13.i26.3540","article-title":"Metabolic liver disease of obesity and role of adipose tissue in the pathogenesis of nonalcoholic fatty liver disease","volume":"13","author":"Qureshi","year":"2007","journal-title":"World J Gastroenterol"},{"key":"2026022209371723700_kfaf176-B54","doi-asserted-by":"publisher","first-page":"146","DOI":"10.1038\/s41540-024-00473-y","article-title":"Mathematical model of the inflammatory response to acute and prolonged lipopolysaccharide exposure in humans","volume":"10","author":"Relouw","year":"2024","journal-title":"NPJ Syst Biol Appl"},{"key":"2026022209371723700_kfaf176-B55","doi-asserted-by":"publisher","first-page":"H1196","DOI":"10.1152\/ajpheart.2000.278.4.H1196","article-title":"Contribution of malonyl-CoA decarboxylase to the high fatty acid oxidation rates seen in the diabetic heart","volume":"278","author":"Sakamoto","year":"2000","journal-title":"Am J Physiol Heart Circ Physiol"},{"key":"2026022209371723700_kfaf176-B56","doi-asserted-by":"publisher","first-page":"511","DOI":"10.1016\/j.csbj.2018.10.013","article-title":"Computational modeling of oxidative stress in fatty livers elucidates the underlying mechanism of the increased susceptibility to ischemia\/reperfusion injury","volume":"16","author":"Schleicher","year":"2018","journal-title":"Comput Struct Biotechnol J"},{"key":"2026022209371723700_kfaf176-B57","doi-asserted-by":"publisher","first-page":"20170443","DOI":"10.1098\/rsif.2017.0443","article-title":"Zonation of hepatic fat accumulation: insights from mathematical modelling of nutrient gradients and fatty acid uptake","volume":"14","author":"Schleicher","year":"2017","journal-title":"J R Soc Interface"},{"key":"2026022209371723700_kfaf176-B58","doi-asserted-by":"publisher","first-page":"231","DOI":"10.1016\/j.freeradbiomed.2008.04.029","article-title":"Fatty acids as modulators of the cellular production of reactive oxygen species","volume":"45","author":"Sch\u00f6nfeld","year":"2008","journal-title":"Free Radic Biol Med"},{"key":"2026022209371723700_kfaf176-B59","doi-asserted-by":"publisher","first-page":"E1084","DOI":"10.1152\/ajpendo.00571.2001","article-title":"A mathematical model of metabolic insulin signaling pathways","volume":"283","author":"Sedaghat","year":"2002","journal-title":"Am J Physiol Endocrinol Metab"},{"key":"2026022209371723700_kfaf176-B4496162","author":"Sharma","year":"2023","journal-title":"StatPearls [Internet]"},{"key":"2026022209371723700_kfaf176-B6952603","doi-asserted-by":"publisher","first-page":"613","DOI":"10.1016\/j.redox.2016.12.035","article-title":"Hydrogen peroxide as a Central redox signaling molecule in physiological oxidative stress: oxidative eustress","volume":"11","author":"Sies","year":"2017","journal-title":"Redox Biol"},{"key":"2026022209371723700_kfaf176-B61","doi-asserted-by":"publisher","first-page":"102402","DOI":"10.1016\/j.clinre.2024.102402","article-title":"Liver tissue lipids in metabolic dysfunction-associated steatotic liver disease with diabetes and obesity","volume":"48","author":"Sourianarayanane","year":"2024","journal-title":"Clin Res Hepatol Gastroenterol"},{"key":"2026022209371723700_kfaf176-B62","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1186\/s12953-018-0131-y","article-title":"Proteomic identification and characterization of hepatic glyoxalase 1 dysregulation in non-alcoholic fatty liver disease","volume":"16","author":"Spanos","year":"2018","journal-title":"Proteome Sci"},{"issue":"323.","key":"2026022209371723700_kfaf176-B0488948","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-018-0377-4","article-title":"Kupffer cell-derived TNF-\u03b1 promotes hepatocytes to produce CXCL1 AND mobilize neutrophils in response to necrotic cells","volume":"9","author":"Su","year":"2018","journal-title":"Cell Death Dis"},{"key":"2026022209371723700_kfaf176-B63","first-page":"817","article-title":"Blood lactate levels after all-out exercise depend on body fat percentage in korean college students","volume":"45","author":"Sung","year":"2016","journal-title":"Iran J Public Health"},{"key":"2026022209371723700_kfaf176-B65","doi-asserted-by":"publisher","first-page":"373","DOI":"10.1161\/ATVBAHA.118.311931","article-title":"Critical role of SREBP-1c large-VLDL pathway in environment-induced hypertriglyceridemia of apo AV deficiency","volume":"39","author":"Takanashi","year":"2019","journal-title":"Arterioscler Thromb Vasc Biol"},{"key":"2026022209371723700_kfaf176-B66","doi-asserted-by":"publisher","first-page":"1836","DOI":"10.1002\/hep.24001","article-title":"Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis","volume":"52","author":"Tilg","year":"2010","journal-title":"Hepatology"},{"key":"2026022209371723700_kfaf176-B67","doi-asserted-by":"publisher","first-page":"191","DOI":"10.1007\/s13679-023-00519-y","article-title":"The role of tumor necrosis factor-alpha in the pathogenesis and treatment of nonalcoholic fatty liver disease","volume":"12","author":"Vachliotis","year":"2023","journal-title":"Curr Obes Rep"},{"issue":":","key":"2026022209371723700_kfaf176-B3667961","doi-asserted-by":"publisher","first-page":"261","DOI":"10.1042\/CS20030285","article-title":"Oxidative stress-related parameters in the liver of non-alcoholic fatty liver disease patients","volume":"106","author":"Videla","year":"2004","journal-title":"Clin Sci (Lond)"},{"issue":":","key":"2026022209371723700_kfaf176-B91126909","doi-asserted-by":"publisher","first-page":"e0143380","DOI":"10.1371\/journal.pone.0143380","article-title":"Peripheral and hepatic vein cytokine levels in correlation with non-alcoholic fatty liver disease (NAFLD)-related metabolic, histological, and haemodynamic features","volume":"10","author":"Vonghia","year":"2015","journal-title":"PLoS One"},{"key":"2026022209371723700_kfaf176-B68","doi-asserted-by":"publisher","first-page":"5726","DOI":"10.18632\/aging.102155","article-title":"Conserved roles of glucose in suppressing reactive oxygen species-induced cell death and animal survival","volume":"11","author":"Wang","year":"2019","journal-title":"Aging (Albany NY)"},{"issue":":","key":"2026022209371723700_kfaf176-B75498609","doi-asserted-by":"publisher","first-page":"21506","DOI":"10.1074\/jbc.M412989200","article-title":"Increased very low density lipoprotein secretion and gonadal fat mass in mice overexpressing liver DGAT1","volume":"280","author":"Yamazaki","year":"2005","journal-title":"J Biol Chem"},{"key":"2026022209371723700_kfaf176-B69","doi-asserted-by":"publisher","first-page":"329","DOI":"10.1038\/s41586-020-2280-2","article-title":"Structure and mechanism of human diacylglycerol O-acyltransferase 1","volume":"581","author":"Wang","year":"2020","journal-title":"Nature"},{"key":"2026022209371723700_kfaf176-B72","doi-asserted-by":"publisher","first-page":"1335","DOI":"10.1097\/HEP.0000000000000004","article-title":"The global epidemiology of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH): a systematic review","volume":"77","author":"Younossi","year":"2023","journal-title":"Hepatology"},{"key":"2026022209371723700_kfaf176-B73","doi-asserted-by":"publisher","first-page":"5832","DOI":"10.1038\/srep05832","article-title":"Association between serum free fatty acid levels and nonalcoholic fatty liver disease: a cross-sectional study","volume":"4","author":"Zhang","year":"2014","journal-title":"Sci Rep"},{"key":"2026022209371723700_kfaf176-B74","doi-asserted-by":"publisher","first-page":"168","DOI":"10.1007\/s00018-023-04820-w","article-title":"TRIM21 ameliorates hepatic glucose and lipid metabolic disorders in type 2 diabetes mellitus by ubiquitination of PEPCK1 and FASN","volume":"80","author":"Zhang","year":"2023","journal-title":"Cell Mol Life Sci"},{"key":"2026022209371723700_kfaf176-B75","doi-asserted-by":"publisher","first-page":"56","DOI":"10.3892\/br.2021.1432","article-title":"Effect of oxymatrine on liver gluconeogenesis is associated with the regulation of PEPCK and G6Pase expression and AKT phosphorylation","volume":"15","author":"Zhu","year":"2021","journal-title":"Biomed Rep"}],"container-title":["Toxicological Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/toxsci\/advance-article-pdf\/doi\/10.1093\/toxsci\/kfaf176\/65944037\/kfaf176.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/toxsci\/article-pdf\/209\/2\/kfaf176\/65944037\/kfaf176.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/toxsci\/article-pdf\/209\/2\/kfaf176\/65944037\/kfaf176.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,22]],"date-time":"2026-02-22T14:37:23Z","timestamp":1771771043000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/toxsci\/article\/doi\/10.1093\/toxsci\/kfaf176\/8382620"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,17]]},"references-count":78,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2026,2,18]]}},"URL":"https:\/\/doi.org\/10.1093\/toxsci\/kfaf176","relation":{},"ISSN":["1096-6080","1096-0929"],"issn-type":[{"value":"1096-6080","type":"print"},{"value":"1096-0929","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2026,2]]},"published":{"date-parts":[[2025,12,17]]},"article-number":"kfaf176"}}