{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,6]],"date-time":"2026-05-06T14:18:39Z","timestamp":1778077119376,"version":"3.51.4"},"reference-count":68,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2022,8,10]],"date-time":"2022-08-10T00:00:00Z","timestamp":1660089600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["NRF-2019R1A2C2002266"],"award-info":[{"award-number":["NRF-2019R1A2C2002266"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Although recent studies have demonstrated that polychlorinated biphenyls (PCB) exposure leads to toxicant-associated steatohepatitis, the underlying mechanism of this condition remains unsolved. Male C57Bl\/6 mice fed a standard diet (SD) or 60% high fat diet (HFD) were exposed to the nondioxin-like PCB mixture Aroclor1260 or dioxin-like PCB congener PCB126 by intraperitoneal injection for a total of four times for six weeks. We observed hepatic injury, steatosis, inflammation, and fibrosis in not only the Aroclor1260-treated mice fed a HFD but the PCB126-treated mice fed either a SD or a HFD. We also observed that both types of PCB exposure induced hepatic iron overload (HIO). Noticeably, the expression of hepatic lipocalin-2 (LCN2) was significantly increased in the PCB-induced nonalcoholic fatty liver disease (NAFLD)\/nonalcoholic steatohepatitis (NASH) models. The knockdown of LCN2 resulted in improvement of PCB-induced lipid and iron accumulation in vitro, suggesting that LCN2 plays a pivotal role in PCB-induced NAFLD\/NASH. We observed that recombinant FGF21 improved hepatic steatosis and HIO in the PCB-induced NAFLD\/NASH models. Importantly, recombinant FGF21 reduced the PCB-induced overexpression of hepatic LCN2 in vivo and in vitro. Our findings indicate that recombinant FGF21 attenuates PCB-induced NAFLD\/NASH by modulating hepatic lipocalin-2 expression. Our data suggest that hepatic LCN2 might represent a suitable therapeutic target for improving PCB-induced NAFLD\/NASH accompanying HIO.<\/jats:p>","DOI":"10.3390\/ijms23168899","type":"journal-article","created":{"date-parts":[[2022,8,10]],"date-time":"2022-08-10T09:42:56Z","timestamp":1660124576000},"page":"8899","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Recombinant FGF21 Attenuates Polychlorinated Biphenyl-Induced NAFLD\/NASH by Modulating Hepatic Lipocalin-2 Expression"],"prefix":"10.3390","volume":"23","author":[{"given":"Hye Young","family":"Kim","sequence":"first","affiliation":[{"name":"Department of Anatomy and Cell Biology and BK21 Program, Department of Translational Biomedical Science, Dong-A University College of Medicine, Busan 49201, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6809-6737","authenticated-orcid":false,"given":"Young Hyun","family":"Yoo","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Cell Biology and BK21 Program, Department of Translational Biomedical Science, Dong-A University College of Medicine, Busan 49201, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,8,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1851","DOI":"10.1053\/j.gastro.2020.01.052","article-title":"Nonalcoholic Fatty Liver Disease 2020: The State of the Disease","volume":"158","author":"Cotter","year":"2020","journal-title":"Gastroenterology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"101122","DOI":"10.1016\/j.molmet.2020.101122","article-title":"Nonalcoholic Fatty Liver Disease (NAFLD) from Pathogenesis to Treatment Concepts in Humans","volume":"50","author":"Pafili","year":"2021","journal-title":"Mol. Metab."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1820","DOI":"10.1002\/hep.23594","article-title":"Nonalcoholic Fatty Liver Disease and Hepatocellular Carcinoma: A Weighty Connection","volume":"51","author":"Starley","year":"2010","journal-title":"Hepatology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1735","DOI":"10.1289\/ehp.1002720","article-title":"Polychlorinated Biphenyls, Lead, and Mercury are Associated with Liver Disease in American Adults: NHANES 2003\u20132004","volume":"118","author":"Cave","year":"2010","journal-title":"Environ. Health Perspect."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1093\/toxsci\/kfy076","article-title":"Liver Disease in a Residential Cohort with Elevated Polychlorinated Biphenyl Exposures","volume":"164","author":"Clair","year":"2018","journal-title":"Toxicol. Sci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"474","DOI":"10.1002\/hep.23321","article-title":"Toxicant-associated Steatohepatitis in Vinyl Chloride Workers","volume":"51","author":"Cave","year":"2010","journal-title":"Hepatology"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.taap.2018.10.011","article-title":"Polychlorinated Biphenyl Exposures Differentially Regulate Hepatic Metabolism and Pancreatic Function: Implications for Nonalcoholic Steatohepatitis and Diabetes","volume":"363","author":"Shi","year":"2019","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.biopen.2018.05.001","article-title":"AhR Signaling Pathways and Regulatory Functions","volume":"7","author":"Larigot","year":"2018","journal-title":"Biochim. Open"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1186\/s40200-015-0218-2","article-title":"The Effects of PCB126 on Intra-Hepatic Mechanisms Associated with Non Alcoholic Fatty Liver Disease","volume":"14","author":"Boucher","year":"2015","journal-title":"J. Diabetes Metab. Disord."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1093\/toxsci\/kfv215","article-title":"PCB126-Induced Disruption in Gluconeogenesis and Fatty Acid Oxidation Precedes Fatty Liver in Male Rats","volume":"149","author":"Gadupudi","year":"2016","journal-title":"Toxicol. Sci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1093\/toxsci\/kfv250","article-title":"Polychlorinated Biphenyl-Xenobiotic Nuclear Receptor Interactions Regulate Energy Metabolism, Behavior, and Inflammation in Non-Alcoholic-Steatohepatitis","volume":"149","author":"Wahlang","year":"2016","journal-title":"Toxicol. Sci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1093\/toxsci\/kfu083","article-title":"Human Receptor Activation by Aroclor 1260, a Polychlorinated Biphenyl Mixture","volume":"140","author":"Wahlang","year":"2014","journal-title":"Toxicol. Sci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1016\/j.taap.2014.06.019","article-title":"Evaluation of Aroclor 1260 Exposure in a Mouse Model of Diet-Induced Obesity and Non-Alcoholic Fatty Liver Disease","volume":"279","author":"Wahlang","year":"2014","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"87","DOI":"10.3109\/10408449409049308","article-title":"Polychlorinated Biphenyls (PCBs): Environmental Impact, Biochemical and Toxic Responses, and Implications for Risk Assessment","volume":"24","author":"Safe","year":"1994","journal-title":"Crit. Rev. Toxicol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.reprotox.2016.10.001","article-title":"Metabolism Disrupting Chemicals and Metabolic Disorders","volume":"68","author":"Heindel","year":"2017","journal-title":"Reprod. Toxicol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"112","DOI":"10.3389\/fendo.2019.00112","article-title":"Endocrine Disrupting Chemicals: An Occult Mediator of Metabolic Disease","volume":"10","author":"Papalou","year":"2019","journal-title":"Front. Endocrinol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"536","DOI":"10.1016\/j.toxrep.2021.03.010","article-title":"Polychlorinated Biphenyls Altered Gut Microbiome in CAR and PXR Knockout Mice Exhibiting Toxicant-Associated Steatohepatitis","volume":"8","author":"Wahlang","year":"2021","journal-title":"Toxicol. Rep."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"8112","DOI":"10.3748\/wjg.v22.i36.8112","article-title":"Iron and Non-Alcoholic Fatty Liver Disease","volume":"22","author":"Britton","year":"2016","journal-title":"World J. Gastroenterol."},{"key":"ref_19","first-page":"173","article-title":"Iron Overload and Non-Alcoholic Fatty Liver Disease","volume":"42","author":"Datz","year":"2016","journal-title":"Minerva Endocrinol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"920","DOI":"10.1016\/j.jhep.2011.05.008","article-title":"Iron in Fatty Liver and in the Metabolic Syndrome: A Promising Therapeutic Target","volume":"55","author":"Dongiovanni","year":"2011","journal-title":"J. Hepatol."},{"key":"ref_21","first-page":"18","article-title":"Liver Iron Sensing and Body Iron Homeostasis","volume":"133","author":"Wang","year":"2019","journal-title":"Blood J. Am. Soc. Hematol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1374","DOI":"10.1093\/ajcn\/87.5.1374","article-title":"Pathways Underlying Iron Accumulation in Human Nonalcoholic Fatty Liver Disease","volume":"87","author":"Aigner","year":"2008","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"644","DOI":"10.1002\/hep4.1190","article-title":"Hepatic Iron Concentration Correlates with Insulin Sensitivity in Nonalcoholic Fatty Liver Disease","volume":"2","author":"Britton","year":"2018","journal-title":"Hepatol. Commun."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1016\/S0016-5085(98)70482-2","article-title":"Increased Hepatic Iron Concentration in Nonalcoholic Steatohepatitis is Associated with Increased Fibrosis","volume":"114","author":"George","year":"1998","journal-title":"Gastroenterology"},{"key":"ref_25","first-page":"695","article-title":"Iron Overload in Patients with Chronic Liver Disease","volume":"12","author":"Kowdley","year":"2016","journal-title":"Gastroenterol. Hepatol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"12354","DOI":"10.1096\/fj.202000790R","article-title":"Hepatic STAMP2 Mediates Recombinant FGF21-induced Improvement of Hepatic Iron Overload in Nonalcoholic Fatty Liver Disease","volume":"34","author":"Kim","year":"2020","journal-title":"FASEB J."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1182\/blood.V83.3.799.799","article-title":"Identification of Neutrophil Gelatinase-Associated Lipocalin as a Novel Matrix Protein of Specific Granules in Human Neutrophils","volume":"83","author":"Kjeldsen","year":"1994","journal-title":"Blood"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1146\/annurev-nutr-071816-064559","article-title":"Lipocalin 2: An Emerging Player in Iron Homeostasis and Inflammation","volume":"37","author":"Xiao","year":"2017","journal-title":"Annu. Rev. Nutr."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Krizanac, M., Mass Sanchez, P.B., Weiskirchen, R., and Asimakopoulos, A. (2021). A Scoping Review on Lipocalin-2 and its Role in Non-Alcoholic Steatohepatitis and Hepatocellular Carcinoma. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22062865"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"4065","DOI":"10.1172\/JCI42004","article-title":"Lipocalin 2 is Essential for Chronic Kidney Disease Progression in Mice and Humans","volume":"120","author":"Viau","year":"2010","journal-title":"J. Clin. Investig."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"430","DOI":"10.3389\/fphys.2016.00430","article-title":"Lipocalin 2 (LCN2) Expression in Hepatic Malfunction and Therapy","volume":"7","author":"Asimakopoulou","year":"2016","journal-title":"Front. Physiol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"601349","DOI":"10.3389\/fendo.2020.601349","article-title":"FGF19 and FGF21 for the Treatment of NASH\u2014two Sides of the Same Coin? Differential and Overlapping Effects of FGF19 and FGF21 from Mice to Human","volume":"11","author":"Henriksson","year":"2020","journal-title":"Front. Endocrinol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1016\/j.cmet.2013.08.005","article-title":"The Effects of LY2405319, an FGF21 Analog, in Obese Human Subjects with Type 2 Diabetes","volume":"18","author":"Gaich","year":"2013","journal-title":"Cell Metab."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1627","DOI":"10.1172\/JCI23606","article-title":"FGF-21 as a Novel Metabolic Regulator","volume":"115","author":"Kharitonenkov","year":"2005","journal-title":"J. Clin. Investig."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"168","DOI":"10.3389\/fendo.2015.00168","article-title":"Fibroblast Growth Factor 21 Analogs for Treating Metabolic Disorders","volume":"6","author":"Zhang","year":"2015","journal-title":"Front. Endocrinol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"e153640","DOI":"10.1172\/JCI153640","article-title":"Targeting Adipose Tissue to Tackle NASH: SPARCL1 as an Emerging Player","volume":"131","author":"Rodrigues","year":"2021","journal-title":"J. Clin. Investig."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1038\/s41423-020-00579-3","article-title":"Immunological Mechanisms and Therapeutic Targets of Fatty Liver Diseases","volume":"18","author":"Wang","year":"2021","journal-title":"Cell. Mol. Immunol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1247","DOI":"10.1007\/s00044-020-02581-w","article-title":"Dioxin-Like and Non-Dioxin-Like PCBs Differentially Regulate the Hepatic Proteome and Modify Diet-Induced Nonalcoholic Fatty Liver Disease Severity","volume":"29","author":"Jin","year":"2020","journal-title":"Med. Chem. Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"106941","DOI":"10.1016\/j.envint.2021.106941","article-title":"A Review of Environmental Metabolism Disrupting Chemicals and Effect Biomarkers Associating Disease Risks: Where Exposomics Meets Metabolomics","volume":"158","author":"Sun","year":"2022","journal-title":"Environ. Int."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"046001","DOI":"10.1289\/EHP10092","article-title":"Exposure to Per-and Polyfluoroalkyl Substances and Markers of Liver Injury: A Systematic Review and Meta-Analysis","volume":"130","author":"Costello","year":"2022","journal-title":"Environ. Health Perspect."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1186\/s12940-015-0066-z","article-title":"Persistent Organic Pollutants and Non-Alcoholic Fatty Liver Disease in Morbidly Obese Patients: A Cohort Study","volume":"14","author":"Rantakokko","year":"2015","journal-title":"Environ. Health"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1007\/s40572-017-0166-8","article-title":"Persistent Endocrine-Disrupting Chemicals and Fatty Liver Disease","volume":"4","author":"Deierlein","year":"2017","journal-title":"Curr. Environ. Health Rep."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.cotox.2019.06.001","article-title":"Polychlorinated Biphenyls and Nonalcoholic Fatty Liver Disease","volume":"14","author":"Wahlang","year":"2019","journal-title":"Curr. Opin. Toxicol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1289\/ehp.0901321","article-title":"Persistent Organic Pollutant Exposure Leads to Insulin Resistance Syndrome","volume":"118","author":"Ruzzin","year":"2010","journal-title":"Environ. Health Perspect."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"293","DOI":"10.15403\/jgld.2014.1121.243.hak","article-title":"The Relationship of Serum Hemojuvelin and Hepcidin Levels with Iron Overload in Nonalcoholic Fatty Liver Disease","volume":"24","author":"Boga","year":"2015","journal-title":"J. Gastrointestin Liver Dis."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/S0168-8278(02)00331-8","article-title":"Serum Thioredoxin Levels as a Predictor of Steatohepatitis in Patients with Nonalcoholic Fatty Liver Disease","volume":"38","author":"Sumida","year":"2003","journal-title":"J. Hepatol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1251","DOI":"10.1111\/j.1572-0241.2007.01192.x","article-title":"Iron Depletion by Phlebotomy Improves Insulin Resistance in Patients with Nonalcoholic Fatty Liver Disease and Hyperferritinemia: Evidence from a Case-Control Study","volume":"102","author":"Valenti","year":"2007","journal-title":"Off. J. Am. Coll. Gastroenterol. ACG"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1188","DOI":"10.1111\/j.1872-034X.2010.00724.x","article-title":"Restriction of Calorie and Iron Intake Results in Reduction of Visceral Fat and Serum Alanine Aminotransferase and Ferritin Levels in Patients with Chronic Liver Disease","volume":"40","author":"Iwasa","year":"2010","journal-title":"Hepatol. Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1146\/annurev.nutr.012809.104804","article-title":"Iron Homeostasis and the Inflammatory Response","volume":"30","year":"2010","journal-title":"Annu. Rev. Nutr."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1016\/j.gene.2013.09.023","article-title":"PCB-77 Disturbs Iron Homeostasis through Regulating Hepcidin Gene Expression","volume":"532","author":"Wang","year":"2013","journal-title":"Gene"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1016\/j.jes.2015.06.001","article-title":"New Insights into Disruption of Iron Homeostasis by Environmental Pollutants","volume":"34","author":"Wang","year":"2015","journal-title":"J. Environ. Sci."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1177\/0036850419826802","article-title":"Endocrine Disrupting Chemicals: Impact on Human Health, Wildlife and the Environment","volume":"102","author":"Pais","year":"2019","journal-title":"Sci. Prog."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"113382","DOI":"10.1016\/j.ecoenv.2022.113382","article-title":"The Associations between Endocrine Disrupting Chemicals and Markers of Inflammation and Immune Responses: A Systematic Review and Meta-Analysis","volume":"234","author":"Liu","year":"2022","journal-title":"Ecotoxicol. Environ. Saf."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.livres.2020.02.003","article-title":"The Alteration of Immune Cells in the Pathogenesis of Non-Alcoholic Fatty Liver Disease and Non-Alcoholic Steatohepatitis","volume":"4","author":"Feng","year":"2020","journal-title":"Liver Res."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1473","DOI":"10.2353\/ajpath.2009.080999","article-title":"Increased Hepatic Myeloperoxidase Activity in Obese Subjects with Nonalcoholic Steatohepatitis","volume":"175","author":"Rensen","year":"2009","journal-title":"Am. J. Pathol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1189\/jlb.0712349","article-title":"Myeloperoxidase: A Front-line Defender Against Phagocytosed Microorganisms","volume":"93","author":"Klebanoff","year":"2013","journal-title":"J. Leukoc. Biol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1620\/tjem.222.319","article-title":"Increased Urinary Lipocalin-2 Reflects Matrix Metalloproteinase-9 Activity in Chronic Hepatitis C with Hepatic Fibrosis","volume":"222","author":"Kim","year":"2010","journal-title":"Tohoku J. Exp. Med."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"660","DOI":"10.1016\/j.bbadis.2013.01.014","article-title":"Protective Effects of Lipocalin-2 (LCN2) in Acute Liver Injury Suggest a Novel Function in Liver Homeostasis","volume":"1832","author":"Zimmermann","year":"2013","journal-title":"Biochim. Biophys. Acta (BBA) Mol. Basis Dis."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1007\/s10534-016-9925-5","article-title":"Lipocalin 2 Alleviates Iron Toxicity by Facilitating Hypoferremia of Inflammation and Limiting Catalytic Iron Generation","volume":"29","author":"Xiao","year":"2016","journal-title":"Biometals"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"988","DOI":"10.1016\/j.jhep.2016.05.041","article-title":"Lipocalin-2 Mediates Non-Alcoholic Steatohepatitis by Promoting Neutrophil-Macrophage Crosstalk Via the Induction of CXCR2","volume":"65","author":"Ye","year":"2016","journal-title":"J. Hepatol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"872","DOI":"10.1016\/j.jhep.2015.11.037","article-title":"Lipocalin 2 Drives Neutrophilic Inflammation in Alcoholic Liver Disease","volume":"64","author":"Wieser","year":"2016","journal-title":"J. Hepatol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"872","DOI":"10.2337\/db09-1541","article-title":"Lipocalin-2 Deficiency Attenuates Insulin Resistance Associated with Aging and Obesity","volume":"59","author":"Law","year":"2010","journal-title":"Diabetes"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1605","DOI":"10.2337\/dbi20-0025","article-title":"A New FGF21 Analog for the Treatment of Fatty Liver Disease","volume":"69","author":"Kleinert","year":"2020","journal-title":"Diabetes"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1007\/s11010-016-2774-2","article-title":"FGF21 Ameliorates Nonalcoholic Fatty Liver Disease by Inducing Autophagy","volume":"420","author":"Zhu","year":"2016","journal-title":"Mol. Cell. Biochem."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"250","DOI":"10.2337\/db08-0392","article-title":"Fibroblast Growth Factor 21 Reverses Hepatic Steatosis, Increases Energy Expenditure, and Improves Insulin Sensitivity in Diet-Induced Obese Mice","volume":"58","author":"Xu","year":"2009","journal-title":"Diabetes"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"601290","DOI":"10.3389\/fendo.2020.601290","article-title":"FGF21: An Emerging Therapeutic Target for Non-Alcoholic Steatohepatitis and Related Metabolic Diseases","volume":"11","author":"Tillman","year":"2020","journal-title":"Front. Endocrinol."},{"key":"ref_67","unstructured":"National Toxicology Program (2006). Toxicology and Carcinogenesis Studies of a Binary Mixture of 3,3\u2032,4,4\u2032,5-Pentachlorobiphenyl (PCB 126) (Cas no. 57465-28-8) and 2,2\u2032,4,4\u2032,5,5\u2032-Hexachlorobiphenyl (PCB 153) (CAS no. 35065-27-1) in Female Harlan Sprague-Dawley Rats (Gavage Studies). Natl. Toxicol. Program Tech. Rep. Ser., 530, 1\u2013258."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1016\/j.jhep.2015.01.025","article-title":"Hepatic STAMP2 Alleviates High Fat Diet-Induced Hepatic Steatosis and Insulin Resistance","volume":"63","author":"Kim","year":"2015","journal-title":"J. Hepatol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/16\/8899\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:06:41Z","timestamp":1760141201000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/16\/8899"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,8,10]]},"references-count":68,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2022,8]]}},"alternative-id":["ijms23168899"],"URL":"https:\/\/doi.org\/10.3390\/ijms23168899","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,8,10]]}}}