{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T05:09:57Z","timestamp":1789016997751,"version":"build-2803163510"},"reference-count":238,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T00:00:00Z","timestamp":1788480000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Type 2 diabetes mellitus (T2D) is a major and growing global health burden that is associated with substantial cardiovascular, renal, and metabolic complications and is increasingly recognized as a systemic disorder involving multiple organs, particularly the liver. Metabolic dysfunction-associated steatotic liver disease (MASLD) affects more than half of individuals with T2D, and the two conditions have a bidirectional relationship: T2D promotes the development and progression of MASLD, including advanced fibrosis and increased liver-related mortality, while MASLD worsens insulin resistance and metabolic control, favoring the onset of T2D. In this context, the liver is increasingly viewed not only as a metabolic organ but also as an endocrine one, secreting hepatokines that act on distant tissues to regulate insulin sensitivity, inflammation, glucose metabolism, and lipid homeostasis. Through these actions, hepatokines are thought to represent one of the mechanistic links between MASLD and T2D. This narrative review summarizes current evidence on several of the most extensively studied hepatokines, including fibroblast growth factor 21, fetuin-A, fetuin-B, leukocyte cell-derived chemotaxin-2, selenoprotein P, angiopoietin-like proteins, and retinol-binding protein 4. As a distinctive feature, the review also discusses emerging pharmacological strategies targeting hepatokine pathways and evaluates how commonly used antidiabetic therapies may modulate hepatokine secretion.<\/jats:p>","DOI":"10.3390\/ijms27177917","type":"journal-article","created":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T17:25:56Z","timestamp":1788542756000},"page":"7917","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Key Hepatokines Linking MASLD and Type 2 Diabetes: From Pathophysiological Mechanisms to Therapeutic Modulation"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7558-0711","authenticated-orcid":false,"given":"Georgeta Liliana","family":"Foia","sequence":"first","affiliation":[{"name":"Grigore T. Popa University of Medicine and Pharmacy Iasi, 700115 Iasi, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5172-0399","authenticated-orcid":false,"given":"Ancuta","family":"Goriuc","sequence":"additional","affiliation":[{"name":"Grigore T. Popa University of Medicine and Pharmacy Iasi, 700115 Iasi, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0017-9672","authenticated-orcid":false,"given":"Ionut","family":"Luchian","sequence":"additional","affiliation":[{"name":"Grigore T. Popa University of Medicine and Pharmacy Iasi, 700115 Iasi, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2312-6987","authenticated-orcid":false,"given":"Dana Gabriela","family":"Budala","sequence":"additional","affiliation":[{"name":"Grigore T. Popa University of Medicine and Pharmacy Iasi, 700115 Iasi, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vasilica","family":"Toma","sequence":"additional","affiliation":[{"name":"Grigore T. Popa University of Medicine and Pharmacy Iasi, 700115 Iasi, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8089-1787","authenticated-orcid":false,"given":"Maria","family":"Bogdan","sequence":"additional","affiliation":[{"name":"University of Medicine and Pharmacy, 200349 Craiova, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5792-5299","authenticated-orcid":false,"given":"Bogdan","family":"Minea","sequence":"additional","affiliation":[{"name":"Grigore T. 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World Health Organization Diabetes. Available online: https:\/\/www.who.int\/news-room\/fact-sheets\/detail\/diabetes."},{"key":"ref_3","unstructured":"International Diabetes Federation (2025). IDF Diabetes Atlas 2025, International Diabetes Federation."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1514","DOI":"10.1056\/NEJMoa1310799","article-title":"Changes in Diabetes-Related Complications in the United States, 1990\u20132010","volume":"370","author":"Gregg","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1007\/s00125-018-4711-2","article-title":"Global Trends in Diabetes Complications: A Review of Current Evidence","volume":"62","author":"Harding","year":"2019","journal-title":"Diabetologia"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2830","DOI":"10.1038\/s41591-024-03123-2","article-title":"The Burden of Diabetes-Associated Multiple Long-Term Conditions on Years of Life Spent and Lost","volume":"30","author":"Gregg","year":"2024","journal-title":"Nat. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1057","DOI":"10.2337\/dci24-0094","article-title":"Metabolic Dysfunction\u2013Associated Steatotic Liver Disease (MASLD) in People With Diabetes: The Need for Screening and Early Intervention. A Consensus Report of the American Diabetes Association","volume":"48","author":"Cusi","year":"2025","journal-title":"Diabetes Care"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1016\/j.jhep.2019.06.021","article-title":"The Global Epidemiology of NAFLD and NASH in Patients with Type 2 Diabetes: A Systematic Review and Meta-Analysis","volume":"71","author":"Younossi","year":"2019","journal-title":"J. Hepatol."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Nzobokela, J., Muchaili, L., Mwambungu, A., Masenga, S.K., and Kirabo, A. (2025). Pathophysiology and Emerging Biomarkers of Cardiovascular-Renal-Hepato-Metabolic Syndrome. Front. Cardiovasc. Med., 12.","DOI":"10.3389\/fcvm.2025.1661563"},{"key":"ref_10","first-page":"e75993","article-title":"The Bidirectional Relationship Between Type 2 Diabetes and Metabolic Dysfunction-Associated Steatotic Liver Disease: A Retrospective Cohort Study","volume":"16","author":"Williams","year":"2024","journal-title":"Cureus"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1016\/S2213-8587(24)00318-8","article-title":"Metabolic Dysfunction-Associated Steatotic Liver Disease: Heterogeneous Pathomechanisms and Effectiveness of Metabolism-Based Treatment","volume":"13","author":"Stefan","year":"2025","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1339","DOI":"10.1007\/s00592-024-02335-9","article-title":"Hepatokines: Unveiling the Molecular and Cellular Mechanisms Connecting Hepatic Tissue to Insulin Resistance and Inflammation","volume":"61","author":"Miao","year":"2024","journal-title":"Acta Diabetol."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Zhang, H., Zhu, R., Sun, Q., and Du, L. (2025). Research Progress on the Role of FGF21 in Insulin Resistance. Front. Endocrinol., 16.","DOI":"10.3389\/fendo.2025.1619462"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1966","DOI":"10.1097\/HEP.0000000000000520","article-title":"A Multisociety Delphi Consensus Statement on New Fatty Liver Disease Nomenclature","volume":"78","author":"Rinella","year":"2023","journal-title":"Hepatology"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Iwaszko-Sochal, K., Kasztelan-Szczerbi\u0144ska, B., and Cicho\u017c-Lach, H. (2025). Is There a Diagnostic Miracle on the Horizon? Emerging Biomarkers in MASLD. J. Clin. Med., 14.","DOI":"10.3390\/jcm14176148"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"421","DOI":"10.4103\/ijem.IJEM_585_17","article-title":"Nonalcoholic Fatty Liver Disease and Type 2 Diabetes Mellitus","volume":"22","author":"Dharmalingam","year":"2018","journal-title":"Indian J. Endocr. Metab."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1016\/j.jhep.2024.04.031","article-title":"EASL\u2013EASD\u2013EASO Clinical Practice Guidelines on the Management of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD)","volume":"81","author":"Tacke","year":"2024","journal-title":"J. Hepatol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"S47","DOI":"10.1016\/j.jhep.2014.12.012","article-title":"NAFLD: A Multisystem Disease","volume":"62","author":"Byrne","year":"2015","journal-title":"J. Hepatol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1136\/gutjnl-2023-330595","article-title":"MASLD: A Systemic Metabolic Disorder with Cardiovascular and Malignant Complications","volume":"73","author":"Targher","year":"2024","journal-title":"Gut"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1596","DOI":"10.1038\/s42255-021-00501-9","article-title":"Non-Alcoholic Fatty Liver Disease: The Interplay between Metabolism, Microbes and Immunity","volume":"3","author":"Tilg","year":"2021","journal-title":"Nat. Metab."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"936","DOI":"10.1111\/jgh.13264","article-title":"Nonalcoholic Fatty Liver Disease Is Associated with an Almost Twofold Increased Risk of Incident Type 2 Diabetes and Metabolic Syndrome. Evidence from a Systematic Review and Meta-analysis","volume":"31","author":"Ballestri","year":"2016","journal-title":"J. Gastro Hepatol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1038\/s41575-021-00448-y","article-title":"The Complex Link between NAFLD and Type 2 Diabetes Mellitus\u2014Mechanisms and Treatments","volume":"18","author":"Targher","year":"2021","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1999","DOI":"10.1016\/j.cgh.2024.03.006","article-title":"The Global Epidemiology of Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis Among Patients With Type 2 Diabetes","volume":"22","author":"Younossi","year":"2024","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1343","DOI":"10.1172\/JCI23621","article-title":"Sources of Fatty Acids Stored in Liver and Secreted via Lipoproteins in Patients with Nonalcoholic Fatty Liver Disease","volume":"115","author":"Donnelly","year":"2005","journal-title":"J. Clin. Investig."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1111\/dom.12272","article-title":"Abdominal Subcutaneous Adipose Tissue Insulin Resistance and Lipolysis in Patients with Non-alcoholic Steatohepatitis","volume":"16","author":"Armstrong","year":"2014","journal-title":"Diabetes Obes. Metab."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1453","DOI":"10.1172\/JCI134165","article-title":"Insulin Resistance Drives Hepatic de Novo Lipogenesis in Nonalcoholic Fatty Liver Disease","volume":"130","author":"Smith","year":"2020","journal-title":"J. Clin. Investig."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"726","DOI":"10.1053\/j.gastro.2013.11.049","article-title":"Increased De Novo Lipogenesis Is a Distinct Characteristic of Individuals With Nonalcoholic Fatty Liver Disease","volume":"146","author":"Lambert","year":"2014","journal-title":"Gastroenterology"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1659","DOI":"10.1001\/jama.282.17.1659","article-title":"Alterations in Liver ATP Homeostasis in Human Nonalcoholic Steatohepatitis: A Pilot Study","volume":"282","author":"Chatham","year":"1999","journal-title":"JAMA"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"4447","DOI":"10.1172\/JCI82204","article-title":"Mitochondrial Metabolism Mediates Oxidative Stress and Inflammation in Fatty Liver","volume":"125","author":"Satapati","year":"2015","journal-title":"J. Clin. Investig."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1359","DOI":"10.1136\/gutjnl-2015-309265","article-title":"Screening Diabetic Patients for Non-Alcoholic Fatty Liver Disease with Controlled Attenuation Parameter and Liver Stiffness Measurements: A Prospective Cohort Study","volume":"65","author":"Kwok","year":"2016","journal-title":"Gut"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1053\/j.gastro.2023.04.025","article-title":"Fibrosis Progression Rate in Biopsy-Proven Nonalcoholic Fatty Liver Disease Among People With Diabetes Versus People Without Diabetes: A Multicenter Study","volume":"165","author":"Huang","year":"2023","journal-title":"Gastroenterology"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Tan, Y., He, Q., and Chan, K.H.K. (2023). Identification of Shared Genetic Architecture between Non-Alcoholic Fatty Liver Disease and Type 2 Diabetes: A Genome-Wide Analysis. Front. Endocrinol., 14.","DOI":"10.3389\/fendo.2023.1050049"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Mohiuddin, M.S., Neha, N.T., Mahir, J.U.K., Shakib, F.A.F., Alam, M.A., Wahiduzzaman, M., Barua, R., Shimu, S.J., Rahman, M., and Hossain, M.R. (2025). Metabolic Dysfunction Associated Fatty Liver Disease and Type 2 Diabetes: Pathophysiological Links, Epidemiological Trends, and Clinical Implications. Front. Endocrinol., 16.","DOI":"10.3389\/fendo.2025.1669478"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1038\/nri2925","article-title":"Type 2 Diabetes as an Inflammatory Disease","volume":"11","author":"Donath","year":"2011","journal-title":"Nat. Rev. Immunol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1038\/nrgastro.2016.147","article-title":"NAFLD and Diabetes Mellitus","volume":"14","author":"Tilg","year":"2017","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1007\/s13679-025-00657-5","article-title":"The Intriguing Roles of Cytokines in Metabolic Dysfunction-Associated Steatotic Liver Disease: A Narrative Review","volume":"14","author":"Vachliotis","year":"2025","journal-title":"Curr. Obes. Rep."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Duan, Y., Pan, X., Luo, J., Xiao, X., Li, J., Bestman, P.L., and Luo, M. (2022). Association of Inflammatory Cytokines With Non-Alcoholic Fatty Liver Disease. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.880298"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1649","DOI":"10.2337\/db13-0728","article-title":"LECT2 Functions as a Hepatokine That Links Obesity to Skeletal Muscle Insulin Resistance","volume":"63","author":"Lan","year":"2014","journal-title":"Diabetes"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1078","DOI":"10.1016\/j.cmet.2015.09.023","article-title":"Fetuin B Is a Secreted Hepatocyte Factor Linking Steatosis to Impaired Glucose Metabolism","volume":"22","author":"Meex","year":"2015","journal-title":"Cell Metab."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1279","DOI":"10.1038\/nm.2851","article-title":"Fetuin-A Acts as an Endogenous Ligand of TLR4 to Promote Lipid-Induced Insulin Resistance","volume":"18","author":"Pal","year":"2012","journal-title":"Nat. Med."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Pezzino, S., Puleo, S., Luca, T., Castorina, M., and Castorina, S. (2025). Adipokine and Hepatokines in Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD): Current and Developing Trends. Biomedicines, 13.","DOI":"10.3390\/biomedicines13081854"},{"key":"ref_42","first-page":"e84258","article-title":"Evaluating Hepatokines in the Progression of Non-Alcoholic Fatty Acid Liver Disease by Decoding Liver-Derived Molecular Pathologies","volume":"17","author":"Ahmed","year":"2025","journal-title":"Cureus"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1016\/j.cmet.2010.09.015","article-title":"A Liver-Derived Secretory Protein, Selenoprotein P, Causes Insulin Resistance","volume":"12","author":"Misu","year":"2010","journal-title":"Cell Metab."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1038\/s42255-021-00354-2","article-title":"Metabolic Messengers: FGF21","volume":"3","author":"Flippo","year":"2021","journal-title":"Nat. Metab."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"26687","DOI":"10.1074\/jbc.M704165200","article-title":"Tissue-Specific Expression of \u03b2Klotho and Fibroblast Growth Factor (FGF) Receptor Isoforms Determines Metabolic Activity of FGF19 and FGF21","volume":"282","author":"Kurosu","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"3751","DOI":"10.2337\/db13-0645","article-title":"High Glucose Represses \u03b2-Klotho Expression and Impairs Fibroblast Growth Factor 21 Action in Mouse Pancreatic Islets","volume":"62","author":"So","year":"2013","journal-title":"Diabetes"},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"De Medeiros, S.F., and Maciel, G.A.R. (2026). Relationship Between Adipose Tissue and Liver Dysfunction in Women with Polycystic Ovary Syndrome and Metabolic Syndrome. Metabolites, 16.","DOI":"10.3390\/metabo16060393"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1097\/MOL.0000000000000960","article-title":"Fibroblast Growth Factor 21: Update on Genetics and Molecular Biology","volume":"36","author":"Barros","year":"2025","journal-title":"Curr. Opin. Lipidol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1055\/a-1778-4159","article-title":"FGF21: A Novel Regulator of Glucose and Lipid Metabolism and Whole-Body Energy Balance","volume":"54","year":"2022","journal-title":"Horm. Metab. Res."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1016\/j.cmet.2023.01.006","article-title":"The Role of Hepatokines in NAFLD","volume":"35","author":"Stefan","year":"2023","journal-title":"Cell Metab."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Tillman, E.J., and Rolph, T. (2020). FGF21: An Emerging Therapeutic Target for Non-Alcoholic Steatohepatitis and Related Metabolic Diseases. Front. Endocrinol., 11.","DOI":"10.3389\/fendo.2020.601290"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"e83075","DOI":"10.7554\/eLife.83075","article-title":"FGF21 Protects against Hepatic Lipotoxicity and Macrophage Activation to Attenuate Fibrogenesis in Nonalcoholic Steatohepatitis","volume":"12","author":"Liu","year":"2023","journal-title":"eLife"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/j.taap.2015.11.012","article-title":"Fibroblast Growth Factor 21 Attenuates Hepatic Fibrogenesis through TGF-\u03b2\/Smad2\/3 and NF-\u03baB Signaling Pathways","volume":"290","author":"Xu","year":"2016","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Milani, I., Codini, M., Guarisco, G., Chinucci, M., Gaita, C., Leonetti, F., and Capoccia, D. (2024). Hepatokines and MASLD: The GLP1-Ras-FGF21-Fetuin-A Crosstalk as a Therapeutic Target. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms251910795"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1186\/s12944-020-01225-7","article-title":"Fetuin-a Expression Profile in Mouse and Human Adipose Tissue","volume":"19","author":"Khadir","year":"2020","journal-title":"Lipids Health Dis."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Lanthier, N., Lebrun, V., Molendi-Coste, O., Van Rooijen, N., and Leclercq, I.A. (2022). Liver Fetuin-A at Initiation of Insulin Resistance. Metabolites, 12.","DOI":"10.3390\/metabo12111023"},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Bourebaba, L., and Marycz, K. (2019). Pathophysiological Implication of Fetuin-A Glycoprotein in the Development of Metabolic Disorders: A Concise Review. J. Clin. Med., 8.","DOI":"10.3390\/jcm8122033"},{"key":"ref_58","first-page":"1445","article-title":"Serum Alpha 2-HS-Glycoprotein Is an Inhibitor of the Human Insulin Receptor at the Tyrosine Kinase Level","volume":"7","author":"Srinivas","year":"1993","journal-title":"Mol. Endocrinol."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Kim, T.H., Hong, D.-G., and Yang, Y.M. (2021). Hepatokines and Non-Alcoholic Fatty Liver Disease: Linking Liver Pathophysiology to Metabolism. Biomedicines, 9.","DOI":"10.3390\/biomedicines9121903"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1111\/j.1365-2265.2011.04070.x","article-title":"Serum fetuin-A Concentrations Are Elevated in Subjects with Impaired Glucose Tolerance and Newly Diagnosed Type 2 Diabetes","volume":"75","author":"Ou","year":"2011","journal-title":"Clin. Endocrinol."},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"\u00d6ner-\u0130yido\u011fan, Y., and Ko\u00e7ak, H. (2026). Chymase and Fetuin-A in Metabolic Inflammation: Molecular Pathways Linking to Insulin Resistance. Diabetology, 7.","DOI":"10.3390\/diabetology7020033"},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Iglesias, P. (2025). The Endocrine Role of Hepatokines: Implications for Human Health and Disease. Front. Endocrinol., 16.","DOI":"10.3389\/fendo.2025.1663353"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1007\/s40618-017-0697-8","article-title":"The Association between Circulating Fetuin-A Levels and Type 2 Diabetes Mellitus Risk: Systematic Review and Meta-Analysis of Observational Studies","volume":"41","author":"Roshanzamir","year":"2018","journal-title":"J. Endocrinol. Investig."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1007\/s00592-017-1068-9","article-title":"Fetuin-A Levels and Risk of Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis","volume":"55","author":"Guo","year":"2018","journal-title":"Acta Diabetol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1530\/EJE-17-1053","article-title":"Association of Fetuin-A with Incident Type 2 Diabetes: Results from the MONICA\/KORA Augsburg Study and a Systematic Meta-Analysis","volume":"178","author":"Sujana","year":"2018","journal-title":"Eur. J. Endocrinol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"e13183","DOI":"10.14814\/phy2.13183","article-title":"Interaction between Plasma fetuin-A and Free Fatty Acids Predicts Changes in Insulin Sensitivity in Response to Long-term Exercise","volume":"5","author":"Lee","year":"2017","journal-title":"Physiol. Rep."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"925","DOI":"10.1111\/liv.12478","article-title":"Fetuin-A Negatively Correlates with Liver and Vascular Fibrosis in Nonalcoholic Fatty Liver Disease Subjects","volume":"35","author":"Sato","year":"2015","journal-title":"Liver Int."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"14683","DOI":"10.1038\/s41598-019-51095-y","article-title":"The C-Terminal Region of Human Plasma Fetuin-B Is Dispensable for the Raised-Elephant-Trunk Mechanism of Inhibition of Astacin Metallopeptidases","volume":"9","author":"Guevara","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"E266","DOI":"10.1152\/ajpendo.00262.2017","article-title":"The Hepatokines Fetuin-A and Fetuin-B Are Upregulated in the State of Hepatic Steatosis and May Differently Impact on Glucose Homeostasis in Humans","volume":"314","author":"Peter","year":"2018","journal-title":"Am. J. Physiol.-Endocrinol. Metab."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"e3235","DOI":"10.1210\/clinem\/dgaf073","article-title":"Fetuin B Is Related to Cytokine\/Chemokine and Insulin Signaling in Adipose Tissue and Plasma in Humans","volume":"110","author":"Kemper","year":"2025","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1038\/s41387-021-00174-z","article-title":"Fetuin-B, a Potential Link of Liver-Adipose Tissue Cross Talk during Diet-Induced Weight Loss\u2013Weight Maintenance","volume":"11","author":"Li","year":"2021","journal-title":"Nutr. Diabetes"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1002\/oby.23961","article-title":"Fetuin B in White Adipose Tissue Induces Inflammation and Is Associated with Peripheral Insulin Resistance in Mice and Humans","volume":"32","author":"Pasmans","year":"2024","journal-title":"Obesity"},{"key":"ref_73","doi-asserted-by":"crossref","unstructured":"Pan, X., Kaminga, A.C., Chen, J., Luo, M., and Luo, J. (2020). Fetuin-A and Fetuin-B in Non-Alcoholic Fatty Liver Disease: A Meta-Analysis and Meta-Regression. Int. J. Environ. Res. Public Health, 17.","DOI":"10.3390\/ijerph17082735"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"156697","DOI":"10.1016\/j.cyto.2024.156697","article-title":"Updates on the Role of Leukocyte Cell-Derived Chemotaxin-2 in Inflammation Regulation and Immunomodulation","volume":"181","author":"Lao","year":"2024","journal-title":"Cytokine"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"e0354","DOI":"10.1097\/MD.0000000000010354","article-title":"Circulating LECT2 Levels in Newly Diagnosed Type 2 Diabetes Mellitus and Their Association with Metabolic Parameters: An Observational Study","volume":"97","author":"Zhang","year":"2018","journal-title":"Medicine"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1006\/bbrc.1997.7095","article-title":"Expression of a Neutrophil Chemotactic Protein LECT2 in Human Hepatocytes Revealed by Immunochemical Studies Using Polyclonal and Monoclonal Antibodies to a Recombinant LECT2","volume":"237","author":"Yamagoe","year":"1997","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1507\/endocrj.EJ19-0255","article-title":"Identification of Hepatokines Involved in Pathology of Type 2 Diabetes and Obesity","volume":"66","author":"Misu","year":"2019","journal-title":"Endocr. J."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"2131","DOI":"10.2147\/DMSO.S527941","article-title":"Associations of Leukocyte-Derived Chemotaxin-2 (LECT2) with Insulin Resistance and Metabolic Syndrome in Type 2 Diabetes: A Cross-Sectional Study","volume":"18","author":"Sha","year":"2025","journal-title":"Diabetes Metab. Syndr. Obes."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1430","DOI":"10.1002\/oby.23445","article-title":"Adipose Tissue LECT2 Expression Is Associated with Obesity and Insulin Resistance in K Orean Women","volume":"30","author":"Kim","year":"2022","journal-title":"Obesity"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1007\/s00595-023-02767-w","article-title":"Relationship between the Changes in Hepatokine Levels and Metabolic Effects after Laparoscopic Sleeve Gastrectomy in Severely Obese Patients","volume":"54","author":"Umemura","year":"2024","journal-title":"Surg. Today"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"e4884","DOI":"10.7717\/peerj.4884","article-title":"Does Bariatric Surgery Influence Plasma Levels of Fetuin-A and Leukocyte Cell-Derived Chemotaxin-2 in Patients with Type 2 Diabetes Mellitus?","volume":"6","author":"Huang","year":"2018","journal-title":"PeerJ"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1248\/bpb.b18-00549","article-title":"Circulating Concentrations of Insulin Resistance-Associated Hepatokines, Selenoprotein P and Leukocyte Cell-Derived Chemotaxin 2, during an Oral Glucose Tolerance Test in Humans","volume":"42","author":"Mohri","year":"2019","journal-title":"Biol. Pharm. Bull."},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"Yoo, H.J., Hwang, S.Y., Choi, J.-H., Lee, H.J., Chung, H.S., Seo, J.-A., Kim, S.G., Kim, N.H., Baik, S.H., and Choi, D.S. (2017). Association of Leukocyte Cell-Derived Chemotaxin 2 (LECT2) with NAFLD, Metabolic Syndrome, and Atherosclerosis. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0174717"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1038\/s41598-020-80689-0","article-title":"LECT2 as a Hepatokine Links Liver Steatosis to Inflammation via Activating Tissue Macrophages in NASH","volume":"11","author":"Takata","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/j.bcp.2015.08.098","article-title":"A Dipeptidyl Peptidase-IV Inhibitor Improves Hepatic Steatosis and Insulin Resistance by AMPK-Dependent and JNK-Dependent Inhibition of LECT2 Expression","volume":"98","author":"Hwang","year":"2015","journal-title":"Biochem. Pharmacol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/j.bbrc.2021.11.038","article-title":"Endoplasmic Reticulum Stress Increases LECT2 Expression via ATF4","volume":"585","author":"Park","year":"2021","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1111\/liv.14816","article-title":"Leukocyte Cell-derived Chemotaxin 2 Promotes the Development of Nonalcoholic Fatty Liver Disease through STAT-1 Pathway in Mice","volume":"41","author":"Wang","year":"2021","journal-title":"Liver Int."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"bqae059","DOI":"10.1210\/endocr\/bqae059","article-title":"LECT2 Deletion Exacerbates Liver Steatosis and Macrophage Infiltration in a Male Mouse Model of LPS-Mediated NASH","volume":"165","author":"Tanida","year":"2024","journal-title":"Endocrinology"},{"key":"ref_89","doi-asserted-by":"crossref","unstructured":"Du\u021b\u0103, C., Muscurel, C., Dogaru, C.B., and Stoian, I. (2025). Selenoproteins: Zoom-In to Their Metal-Binding Properties in Neurodegenerative Diseases. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26031305"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"1424","DOI":"10.1016\/j.bbagen.2009.05.014","article-title":"Eukaryotic Selenoproteins and Selenoproteomes","volume":"1790","author":"Lobanov","year":"2009","journal-title":"Biochim. Et Biophys. Acta (BBA) General. Subj."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1016\/j.freeradbiomed.2018.02.030","article-title":"Selenium, Selenoprotein P, and Alzheimer\u2019s Disease: Is There a Link?","volume":"127","author":"Solovyev","year":"2018","journal-title":"Free Radic. Biol. Med."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"E1325","DOI":"10.1210\/jc.2011-0620","article-title":"Serum Selenoprotein P Levels in Patients with Type 2 Diabetes and Prediabetes: Implications for Insulin Resistance, Inflammation, and Atherosclerosis","volume":"96","author":"Yang","year":"2011","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_93","first-page":"e103942","article-title":"Selenoprotein P as a Biomarker for Microvascular Complications in Type 2 Diabetes Mellitus: A Cross-Sectional Study in South India","volume":"18","author":"Vaithinathan","year":"2026","journal-title":"Cureus"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"532","DOI":"10.1111\/jdi.13699","article-title":"Effects of Eicosapentaenoic Acid on Serum Levels of Selenoprotein P and Organ-specific Insulin Sensitivity in Humans with Dyslipidemia and Type 2 Diabetes","volume":"13","author":"Takeshita","year":"2022","journal-title":"J. Diabetes Investig."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"516","DOI":"10.1016\/j.clinre.2017.01.005","article-title":"Evaluation of Endothelial Dysfunction in Patients with Nonalcoholic Fatty Liver Disease: Association of Selenoprotein P with Carotid Intima-Media Thickness and Endothelium-Dependent Vasodilation","volume":"41","author":"Kara","year":"2017","journal-title":"Clin. Res. Hepatol. Gastroenterol."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"63","DOI":"10.4093\/dmj.2013.37.1.63","article-title":"Increased Selenoprotein P Levels in Subjects with Visceral Obesity and Nonalcoholic Fatty Liver Disease","volume":"37","author":"Choi","year":"2013","journal-title":"Diabetes Metab. J."},{"key":"ref_97","doi-asserted-by":"crossref","unstructured":"Caviglia, G.P., Rosso, C., Armandi, A., Gaggini, M., Carli, F., Abate, M.L., Olivero, A., Ribaldone, D.G., Saracco, G.M., and Gastaldelli, A. (2020). Interplay between Oxidative Stress and Metabolic Derangements in Non-Alcoholic Fatty Liver Disease: The Role of Selenoprotein P. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21228838"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"3800","DOI":"10.1002\/jcp.30121","article-title":"SeP Is Elevated in NAFLD and Participates in NAFLD Pathogenesis through AMPK\/ACC Pathway","volume":"236","author":"Chen","year":"2021","journal-title":"J. Cell. Physiol."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"598","DOI":"10.1055\/a-0811-9136","article-title":"Selenoprotein P in Patients with Nonalcoholic Fatty Liver Disease","volume":"127","author":"Polyzos","year":"2019","journal-title":"Exp. Clin. Endocrinol. Diabetes"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/j.cmet.2022.12.001","article-title":"Effect of Alternate Day Fasting Combined with Aerobic Exercise on Non-Alcoholic Fatty Liver Disease: A Randomized Controlled Trial","volume":"35","author":"Ezpeleta","year":"2023","journal-title":"Cell Metab."},{"key":"ref_101","doi-asserted-by":"crossref","unstructured":"Hegazy, M.A., Mohamed, S.S., Saad, E.H., Abdelghani, A., El Fattah, D.A., Mekki, M.A.E., Fathy, M., Hassan, N., and Ashoush, O. (2026). Selenoprotein P Deficiency in MASLD: Association with Insulin Resistance and Liver Fibrosis: A Prospective Case-Control Study. BMC Gastroenterol., 26.","DOI":"10.1186\/s12876-026-04817-2"},{"key":"ref_102","doi-asserted-by":"crossref","unstructured":"Santulli, G. (2014). Angiopoietin-Like Proteins: A Comprehensive Look. Front. Endocrinol., 5.","DOI":"10.3389\/fendo.2014.00004"},{"key":"ref_103","first-page":"1736","article-title":"Angiopoietin-Like Proteins: Cardiovascular Biology and Therapeutic Targeting for the Prevention of Cardiovascular Diseases","volume":"39","author":"Thorin","year":"2023","journal-title":"Can. J. Cardiol."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.cca.2021.06.024","article-title":"Angiopoietin-like Proteins in Atherosclerosis","volume":"521","author":"Liu","year":"2021","journal-title":"Clin. Chim. Acta"},{"key":"ref_105","doi-asserted-by":"crossref","unstructured":"Ramos, P., Shi, Q., Kleberg, J., Maharjan, C.K., Zhang, W., and Kolb, R. (2025). ANGPTL4: A Comprehensive Review of 25 Years of Research. Cancers, 17.","DOI":"10.3390\/cancers17142364"},{"key":"ref_106","doi-asserted-by":"crossref","unstructured":"Younis, O.M., Dhaydel, A.S., Alghwyeen, W.F., Abu Hantash, N.R., Allan, L.M., Qasem, I.M., and Saeed, A. (2025). The Role of ANGPTL4 in Cancer: A Meta-Analysis of Observational Studies and Multi-Omics Investigation. PLoS ONE, 20.","DOI":"10.1371\/journal.pone.0320343"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"908","DOI":"10.1016\/j.jstrokecerebrovasdis.2017.10.033","article-title":"Angiopoietin-Like Proteins 4 (ANGPTL4) Gene Polymorphisms and Risk of Brain Arteriovenous Malformation","volume":"27","author":"Erkinova","year":"2018","journal-title":"J. Stroke Cerebrovasc. Dis."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"2277","DOI":"10.1161\/ATVBAHA.110.212209","article-title":"The Relationship Between Plasma Angiopoietin-like Protein 4 Levels, Angiopoietin-like Protein 4 Genotype, and Coronary Heart Disease Risk","volume":"30","author":"Robciuc","year":"2010","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1186\/s12944-021-01481-1","article-title":"Circulating Angiopoietin-like Proteins in Metabolic-Associated Fatty Liver Disease: A Systematic Review and Meta-Analysis","volume":"20","author":"Ke","year":"2021","journal-title":"Lipids Health Dis."},{"key":"ref_110","doi-asserted-by":"crossref","unstructured":"Abdelhameed, F., Lagojda, L., Kite, C., Dallaway, A., Mustafa, A., Than, N.N., Kassi, E., Randeva, H.S., and Kyrou, I. (2025). Circulating Angiopoietin-like Protein 8 (ANGPTL8) and Steatotic Liver Disease Related to Metabolic Dysfunction: An Updated Systematic Review and Meta-Analysis. Front. Endocrinol., 16.","DOI":"10.3389\/fendo.2025.1574842"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"5096860","DOI":"10.1155\/2019\/5096860","article-title":"The Relationship between Circulating ANGPTL8\/Betatrophin Concentrations and Adult Obesity: A Meta-Analysis","volume":"2019","author":"Ye","year":"2019","journal-title":"Dis. Markers"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1080\/09513590.2018.1536736","article-title":"Circulating Angiopoietin-like 8 Protein (ANGPTL8\/Betatrophin) in Patients with Polycystic Ovary Syndrome: A Systematic Review and Multi Effect Size Meta-Analysis","volume":"35","author":"Varikasuvu","year":"2019","journal-title":"Gynecol. Endocrinol."},{"key":"ref_113","doi-asserted-by":"crossref","unstructured":"Kong, F.-J., Ma, L.-L., Li, G., Chen, Y.-X., and Zhou, J.-Q. (2017). Circulating Betatrophin Levels and Gestational Diabetes Mellitus: A Systematic Review and Meta-Analysis. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0169941"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"6194750","DOI":"10.1155\/2016\/6194750","article-title":"Circulating Betatrophin in Patients with Type 2 Diabetes: A Meta-Analysis","volume":"2016","author":"Li","year":"2016","journal-title":"J. Diabetes Res."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"9391837","DOI":"10.1155\/2016\/9391837","article-title":"The Relationship between Betatrophin Levels in Blood and T2DM: A Systematic Review and Meta-Analysis","volume":"2016","author":"Yue","year":"2016","journal-title":"Dis. Markers"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"201","DOI":"10.23736\/S2724-6507.23.04073-3","article-title":"Association between Circulating Betatrophin Levels and T2DM: A Meta-Analysis","volume":"50","author":"Zhan","year":"2025","journal-title":"Minerva Endocrinol."},{"key":"ref_117","doi-asserted-by":"crossref","unstructured":"Leca, B.M., Kite, C., Lagojda, L., Davasgaium, A., Dallaway, A., Chatha, K.K., Randeva, H.S., and Kyrou, I. (2024). Retinol-Binding Protein 4 (RBP4) Circulating Levels and Gestational Diabetes Mellitus: A Systematic Review and Meta-Analysis. Front. Public Health, 12.","DOI":"10.3389\/fpubh.2024.1348970"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"45100","DOI":"10.1038\/srep45100","article-title":"Retinol Binding Protein-4 Levels and Non-Alcoholic Fatty Liver Disease: A Community-Based Cross-Sectional Study","volume":"7","author":"Chen","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"101590","DOI":"10.1016\/j.tjnut.2026.101590","article-title":"An Association of Elevated Blood Vitamin A Level and Severity of Metabolic Dysfunction\u2013Associated Steatotic Liver Disease in Humans","volume":"156","author":"OuYang","year":"2026","journal-title":"J. Nutr."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"1020","DOI":"10.1007\/s12020-024-03777-5","article-title":"Retinol Binding Protein 4 and Type 2 Diabetes: From Insulin Resistance to Pancreatic \u03b2-Cell Function","volume":"85","author":"Fan","year":"2024","journal-title":"Endocrine"},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s11010-011-0831-4","article-title":"Retinoids Induced Pck1 Expression and Attenuated Insulin-Mediated Suppression of Its Expression via Activation of Retinoic Acid Receptor in Primary Rat Hepatocytes","volume":"355","author":"Zhang","year":"2011","journal-title":"Mol. Cell Biochem."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"15080","DOI":"10.1074\/jbc.M117.782334","article-title":"The Retinol-Binding Protein Receptor STRA6 Regulates Diurnal Insulin Responses","volume":"292","author":"Gliniak","year":"2017","journal-title":"J. Biol. Chem."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"2067","DOI":"10.1007\/s00018-009-0003-9","article-title":"Fibroblast Growth Factor 21: An Overview from a Clinical Perspective","volume":"66","year":"2009","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_124","first-page":"100198","article-title":"Overexpression and Biophysical and Functional Characterization of a Recombinant FGF21","volume":"5","author":"Phan","year":"2025","journal-title":"Biophys. Rep."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"560034","DOI":"10.2147\/DDDT.S560034","article-title":"Fibroblast Growth Factor 21: Mechanisms, Therapeutic Potential, and Clinical Translation in Metabolic Dysfunction","volume":"20","author":"Rama","year":"2026","journal-title":"Drug Des. Dev. Ther."},{"key":"ref_126","doi-asserted-by":"crossref","unstructured":"Spann, R.A., Morrison, C.D., and Den Hartigh, L.J. (2022). The Nuanced Metabolic Functions of Endogenous FGF21 Depend on the Nature of the Stimulus, Tissue Source, and Experimental Model. Front. Endocrinol., 12.","DOI":"10.3389\/fendo.2021.802541"},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"456","DOI":"10.1053\/j.gastro.2010.04.054","article-title":"Increased Fibroblast Growth Factor 21 in Obesity and Nonalcoholic Fatty Liver Disease","volume":"139","author":"Dushay","year":"2010","journal-title":"Gastroenterology"},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1007\/s00125-014-3475-6","article-title":"Fibroblast Growth Factor 21 Participates in Adaptation to Endoplasmic Reticulum Stress and Attenuates Obesity-Induced Hepatic Metabolic Stress","volume":"58","author":"Kim","year":"2015","journal-title":"Diabetologia"},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1007\/s11010-015-2358-6","article-title":"Fibroblast Growth Factor (FGF21) Protects Mouse Liver against d-Galactose-Induced Oxidative Stress and Apoptosis via Activating Nrf2 and PI3K\/Akt Pathways","volume":"403","author":"Yu","year":"2015","journal-title":"Mol. Cell Biochem."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"562","DOI":"10.1016\/j.jhep.2024.04.034","article-title":"FGF21 Agonists: An Emerging Therapeutic for Metabolic Dysfunction-Associated Steatohepatitis and Beyond","volume":"81","author":"Harrison","year":"2024","journal-title":"J. Hepatol."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1016\/j.tem.2024.02.001","article-title":"Current Status and Future Perspectives of FGF21 Analogues in Clinical Trials","volume":"35","author":"Chui","year":"2024","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_132","first-page":"51","article-title":"Efficacy and Safety of Fibroblast Growth Factor 21 Analogues for Metabolic Dysfunction-Associated Steatohepatitis: A Systematic Review and Meta-Analysis","volume":"81","author":"Khalil","year":"2024","journal-title":"Ann. Nutr. Metab."},{"key":"ref_133","doi-asserted-by":"crossref","unstructured":"Chekol Abebe, E., Tilahun Muche, Z., Behaile T\/Mariam, A., Mengie Ayele, T., Mekonnen Agidew, M., Teshome Azezew, M., Abebe Zewde, E., Asmamaw Dejenie, T., and Asmamaw Mengstie, M. (2022). The Structure, Biosynthesis, and Biological Roles of Fetuin-A: A Review. Front. Cell Dev. Biol., 10.","DOI":"10.3389\/fcell.2022.945287"},{"key":"ref_134","doi-asserted-by":"crossref","unstructured":"Kr\u00f3l-Kulikowska, M., Przyborska, A., Miernikiewicz, E., Roszykiewicz, P., Roszykiewicz, W., Banasik, M., and Kepinska, M. (2025). Fetuin-A and Heme Oxygenase 1 as Potential New Markers in the Diagnosis of Diabetic Kidney Disease. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26209862"},{"key":"ref_135","doi-asserted-by":"crossref","unstructured":"Maria Barbalho, S., Laurindo, L.F., Valenti, V.E., M\u00e9ndez-S\u00e1nchez, N., Ram\u00edrez-Mej\u00eda, M.M., and Goulart, R.D.A. (2025). Organokine-Mediated Crosstalk: A Systems Biology Perspective on the Pathogenesis of MASLD\u2014A Narrative Review. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms262311547"},{"key":"ref_136","doi-asserted-by":"crossref","unstructured":"Entuc, A.M., Bogdan, M., Boboc, I.K.S., Tartau, L.M., Pintilei, D.R., Pavel, L.L., Pelin, A.-M., Spinei, A., and Foia, L.G. (2026). Selected Emerging Biomarkers in Type 2 Diabetes Mellitus: Clinical Insights and Implications for Precision Care. Medicina, 62.","DOI":"10.3390\/medicina62010152"},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"1494","DOI":"10.1161\/CIRCRESAHA.110.234260","article-title":"Fetuin-A Regulation of Calcified Matrix Metabolism","volume":"108","author":"Heiss","year":"2011","journal-title":"Circ. Res."},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"116","DOI":"10.5653\/cerm.2018.45.3.116","article-title":"Associations of Serum Fetuin-A and Oxidative Stress Parameters with Polycystic Ovary Syndrome","volume":"45","author":"Sak","year":"2018","journal-title":"Clin. Exp. Reprod. Med."},{"key":"ref_139","doi-asserted-by":"crossref","unstructured":"Elhoseeny, M.M., Abdulaziz, B.A., Mohamed, M.A., Elsharaby, R.M., Rashad, G.M., and Othman, A.A.A. (2024). Fetuin-A: A Relevant Novel Serum Biomarker for Non-Invasive Diagnosis of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD): A Retrospective Case-Control Study. BMC Gastroenterol., 24.","DOI":"10.1186\/s12876-024-03310-y"},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"6657658","DOI":"10.1155\/2021\/6657658","article-title":"Serum Fetuin-B Levels Are Elevated in Women with Metabolic Syndrome and Associated with Increased Oxidative Stress","volume":"2021","author":"Xue","year":"2021","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"17133","DOI":"10.1074\/jbc.M116.720375","article-title":"Crystal Structure of Human Leukocyte Cell-Derived Chemotaxin 2 (LECT2) Reveals a Mechanistic Basis of Functional Evolution in a Mammalian Protein with an M23 Metalloendopeptidase Fold","volume":"291","author":"Zheng","year":"2016","journal-title":"J. Biol. Chem."},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/j.livres.2024.09.004","article-title":"Leukocyte Cell-Derived Chemotaxin 2 (LECT2) Regulates Liver Ischemia\u2013Reperfusion Injury","volume":"8","author":"Dong","year":"2024","journal-title":"Liver Res."},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"160241","DOI":"10.1098\/rsob.160241","article-title":"Human Selenoprotein P and S Variant mRNAs with Different Numbers of SECIS Elements and Inferences from Mutant Mice of the Roles of Multiple SECIS Elements","volume":"6","author":"Wu","year":"2016","journal-title":"Open Biol."},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1042\/BJ20040328","article-title":"Domain Structure of Bi-Functional Selenoprotein P","volume":"381","author":"Saito","year":"2004","journal-title":"Biochem. J."},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"6525449","DOI":"10.1155\/2021\/6525449","article-title":"Lack of Association between Common Polymorphisms in Selenoprotein P Gene and Susceptibility to Colorectal Cancer, Breast Cancer, and Prostate Cancer: A Meta-Analysis","volume":"2021","author":"Xu","year":"2021","journal-title":"BioMed. Res. Int."},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"862","DOI":"10.1016\/j.clnu.2022.02.007","article-title":"Nutritional Status of Selenium in Overweight and Obesity: A Systematic Review and Meta-Analysis","volume":"41","author":"Fontenelle","year":"2022","journal-title":"Clin. Nutr."},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"100150","DOI":"10.1016\/j.jlr.2021.100150","article-title":"Role and Mechanism of the Action of Angiopoietin-like Protein ANGPTL4 in Plasma Lipid Metabolism","volume":"62","author":"Kersten","year":"2021","journal-title":"J. Lipid Res."},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"e2420721122","DOI":"10.1073\/pnas.2420721122","article-title":"ANGPTL3\/8 Is an Atypical Unfoldase That Regulates Intravascular Lipolysis by Catalyzing Unfolding of Lipoprotein Lipase","volume":"122","author":"Kumari","year":"2025","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"E493","DOI":"10.1152\/ajpendo.00195.2021","article-title":"Regulation of Lipoprotein Metabolism by ANGPTL3, ANGPTL4, and ANGPTL8","volume":"321","author":"Davies","year":"2021","journal-title":"Am. J. Physiol.-Endocrinol. Metab."},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"e140989","DOI":"10.1172\/JCI140989","article-title":"Hepatocyte-Specific Suppression of ANGPTL4 Improves Obesity-Associated Diabetes and Mitigates Atherosclerosis in Mice","volume":"131","author":"Singh","year":"2021","journal-title":"J. Clin. Investig."},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"100101","DOI":"10.1016\/j.jlr.2021.100101","article-title":"Antisense Oligonucleotide\u2013Mediated Inhibition of Angiopoietin-like Protein 3 Increases Reverse Cholesterol Transport in Mice","volume":"62","author":"Bell","year":"2021","journal-title":"J. Lipid Res."},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1056\/NEJMoa1001689","article-title":"Cholesterol Efflux Capacity, High-Density Lipoprotein Function, and Atherosclerosis","volume":"364","author":"Khera","year":"2011","journal-title":"N. Engl. J. Med."},{"key":"ref_153","doi-asserted-by":"crossref","unstructured":"Chandrasekaran, P., Weiskirchen, S., and Weiskirchen, R. (2024). Structure, Functions, and Implications of Selected Lipocalins in Human Disease. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25084290"},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1016\/j.freeradbiomed.2022.12.085","article-title":"Exosomal RBP4 Potentiated Hepatic Lipid Accumulation and Inflammation in High-Fat-Diet-Fed Mice by Promoting M1 Polarization of Kupffer Cells","volume":"195","author":"Yao","year":"2023","journal-title":"Free Radic. Biol. Med."},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1038\/nature03711","article-title":"Serum Retinol Binding Protein 4 Contributes to Insulin Resistance in Obesity and Type 2 Diabetes","volume":"436","author":"Yang","year":"2005","journal-title":"Nature"},{"key":"ref_156","doi-asserted-by":"crossref","first-page":"556","DOI":"10.1007\/s12664-021-01176-6","article-title":"Fetuin-A in Newly Detected Type 2 Diabetes Mellitus as a Marker of Non-Alcoholic Fatty Liver Disease","volume":"40","author":"Yamasandhi","year":"2021","journal-title":"Indian J. Gastroenterol."},{"key":"ref_157","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1097\/MEG.0000000000001354","article-title":"Serum Fetuin-B Level Is an Independent Marker for Nonalcoholic Fatty Liver Disease in Patients with Type 2 Diabetes","volume":"31","author":"Ahmed","year":"2019","journal-title":"Eur. J. Gastroenterol. Hepatol."},{"key":"ref_158","doi-asserted-by":"crossref","first-page":"3715026","DOI":"10.1155\/2021\/3715026","article-title":"Liraglutide Decreases Liver Fat Content and Serum Fibroblast Growth Factor 21 Levels in Newly Diagnosed Overweight Patients with Type 2 Diabetes and Nonalcoholic Fatty Liver Disease","volume":"2021","author":"Li","year":"2021","journal-title":"J. Diabetes Res."},{"key":"ref_159","doi-asserted-by":"crossref","unstructured":"Falamarzi, K., Malekpour, M., Tafti, M.F., Azarpira, N., Behboodi, M., and Zarei, M. (2022). The Role of FGF21 and Its Analogs on Liver Associated Diseases. Front. Med., 9.","DOI":"10.3389\/fmed.2022.967375"},{"key":"ref_160","doi-asserted-by":"crossref","unstructured":"Mega, A., Turri, C., Marzi, L., Dauriz, M., Sacco, R., Floreani, A., and Stasi, C. (2026). New Treatment Options for MASLD Patients with Type 2 Diabetes. Life, 16.","DOI":"10.3390\/life16020254"},{"key":"ref_161","doi-asserted-by":"crossref","first-page":"654","DOI":"10.1038\/s41574-020-0386-0","article-title":"The Therapeutic Potential of FGF21 in Metabolic Diseases: From Bench to Clinic","volume":"16","author":"Geng","year":"2020","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_162","doi-asserted-by":"crossref","first-page":"1020","DOI":"10.1016\/j.jhep.2010.11.007","article-title":"Risk of Chronic Kidney Disease in Patients with Non-Alcoholic Fatty Liver Disease: Is There a Link?","volume":"54","author":"Targher","year":"2011","journal-title":"J. Hepatol."},{"key":"ref_163","doi-asserted-by":"crossref","first-page":"9084","DOI":"10.3390\/cimb45110570","article-title":"The Interconnection between Hepatic Insulin Resistance and Metabolic Dysfunction-Associated Steatotic Liver Disease\u2014The Transition from an Adipocentric to Liver-Centric Approach","volume":"45","author":"Macut","year":"2023","journal-title":"Curr. Issues Mol. Biol."},{"key":"ref_164","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_165","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1016\/j.cmet.2016.02.001","article-title":"A Long-Acting FGF21 Molecule, PF-05231023, Decreases Body Weight and Improves Lipid Profile in Non-Human Primates and Type 2 Diabetic Subjects","volume":"23","author":"Talukdar","year":"2016","journal-title":"Cell Metab."},{"key":"ref_166","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1016\/j.cmet.2019.01.004","article-title":"A Dozen Years of Discovery: Insights into the Physiology and Pharmacology of FGF21","volume":"29","author":"Kliewer","year":"2019","journal-title":"Cell Metab."},{"key":"ref_167","doi-asserted-by":"crossref","unstructured":"Cui, X., Sun, Q., and Wang, H. (2025). Targeting Fibroblast Growth Factor (FGF)-21: A Promising Strategy for Metabolic Dysfunction-Associated Steatotic Liver Disease Treatment. Front. Pharmacol., 16.","DOI":"10.3389\/fphar.2025.1510322"},{"key":"ref_168","doi-asserted-by":"crossref","unstructured":"Casta\u00f1\u00e9, H., Jim\u00e9nez-Franco, A., Onoiu, A.-I., Cambra-Cort\u00e9s, V., Hern\u00e1ndez-Aguilera, A., Parada, D., Riu, F., Zorzano, A., Camps, J., and Joven, J. (2025). Dysregulation of the FGF21\u2013Adiponectin Axis in a Large Cohort of Patients with Severe Obesity and Liver Disease. Int. J. Mol. Sci., 26.","DOI":"10.20944\/preprints202507.1768.v1"},{"key":"ref_169","doi-asserted-by":"crossref","first-page":"1080","DOI":"10.1016\/S2468-1253(23)00272-8","article-title":"Safety and Efficacy of Once-Weekly Efruxifermin versus Placebo in Non-Alcoholic Steatohepatitis (HARMONY): A Multicentre, Randomised, Double-Blind, Placebo-Controlled, Phase 2b Trial","volume":"8","author":"Harrison","year":"2023","journal-title":"Lancet Gastroenterol. Hepatol."},{"key":"ref_170","doi-asserted-by":"crossref","first-page":"998","DOI":"10.1056\/NEJMoa2304286","article-title":"Randomized, Controlled Trial of the FGF21 Analogue Pegozafermin in NASH","volume":"389","author":"Loomba","year":"2023","journal-title":"N. Engl. J. Med."},{"key":"ref_171","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1007\/s11892-026-01621-w","article-title":"Pharmacologic Treatment of Metabolic Dysfunction-Associated Steatotic Liver Disease in the Context of Type 2 Diabetes","volume":"26","author":"Malandris","year":"2026","journal-title":"Curr. Diab Rep."},{"key":"ref_172","doi-asserted-by":"crossref","first-page":"1248","DOI":"10.1016\/j.metabol.2008.04.019","article-title":"Effects of Pioglitazone on Serum Fetuin-A Levels in Patients with Type 2 Diabetes Mellitus","volume":"57","author":"Mori","year":"2008","journal-title":"Metabolism"},{"key":"ref_173","doi-asserted-by":"crossref","unstructured":"Ochi, A., Mori, K., Emoto, M., Nakatani, S., Morioka, T., Motoyama, K., Fukumoto, S., Imanishi, Y., Koyama, H., and Ishimura, E. (2014). Direct Inhibitory Effects of Pioglitazone on Hepatic Fetuin-A Expression. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0088704"},{"key":"ref_174","doi-asserted-by":"crossref","first-page":"42156","DOI":"10.1038\/s41598-025-26018-9","article-title":"Independent Effects of Metformin and Dapagliflozin on Fetuin-A, Hepatic and Pancreatic Fat, and Hepatic Fibrosis in Asian Indians with Type 2 Diabetes","volume":"15","author":"Dutta","year":"2025","journal-title":"Sci. Rep."},{"key":"ref_175","doi-asserted-by":"crossref","first-page":"1547","DOI":"10.1056\/NEJMoa2036205","article-title":"A Randomized, Controlled Trial of the Pan-PPAR Agonist Lanifibranor in NASH","volume":"385","author":"Francque","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_176","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1038\/nrendo.2012.258","article-title":"The Role of Hepatokines in Metabolism","volume":"9","author":"Stefan","year":"2013","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_177","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1016\/j.dsx.2014.09.009","article-title":"Comparative Effects of Metformin and Pioglitazone on Fetuin-A and Osteoprotegerin Concentrations in Patients with Newly Diagnosed Diabetes: A Randomized Clinical Trial","volume":"9","author":"Esteghamati","year":"2015","journal-title":"Diabetes Metab. Syndr. Clin. Res. Rev."},{"key":"ref_178","doi-asserted-by":"crossref","first-page":"12869","DOI":"10.1038\/s41598-022-17000-w","article-title":"Hepatokine Fetuin B Expression Is Regulated by Leptin-STAT3 Signalling and Associated with Leptin in Obesity","volume":"12","author":"Wang","year":"2022","journal-title":"Sci. Rep."},{"key":"ref_179","doi-asserted-by":"crossref","first-page":"114886","DOI":"10.1016\/j.yexcr.2026.114886","article-title":"Fetuin B Drives Metabolism-Associated Steatohepatitis by Promoting Hepatocyte Pyroptosis via NLRP3\/GSDMD Pathway","volume":"456","author":"Chen","year":"2026","journal-title":"Exp. Cell Res."},{"key":"ref_180","doi-asserted-by":"crossref","first-page":"S32","DOI":"10.3350\/cmh.2024.0431","article-title":"Epidemiology of Metabolic Dysfunction-Associated Steatotic Liver Disease","volume":"31","author":"Younossi","year":"2025","journal-title":"Clin. Mol. Hepatol."},{"key":"ref_181","doi-asserted-by":"crossref","first-page":"17562848241276334","DOI":"10.1177\/17562848241276334","article-title":"Modernizing Metabolic Dysfunction-Associated Steatotic Liver Disease Diagnostics: The Progressive Shift from Liver Biopsy to Noninvasive Techniques","volume":"17","author":"Hudson","year":"2024","journal-title":"Ther. Adv. Gastroenterol."},{"key":"ref_182","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.ejim.2024.01.013","article-title":"Non-Invasive Testing and Risk-Stratification in Patients with MASLD","volume":"122","author":"Liguori","year":"2024","journal-title":"Eur. J. Intern. Med."},{"key":"ref_183","doi-asserted-by":"crossref","first-page":"1658","DOI":"10.1038\/s41467-017-01863-z","article-title":"Selenoprotein P-Neutralizing Antibodies Improve Insulin Secretion and Glucose Sensitivity in Type 2 Diabetes Mouse Models","volume":"8","author":"Mita","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_184","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1186\/s12944-024-02352-1","article-title":"ANGPTL3 as a Target for Treating Lipid Disorders in Type 2 Diabetes Patients","volume":"23","author":"Chen","year":"2024","journal-title":"Lipids Health Dis."},{"key":"ref_185","doi-asserted-by":"crossref","first-page":"2383","DOI":"10.1056\/NEJMoa1409065","article-title":"HDL Cholesterol Efflux Capacity and Incident Cardiovascular Events","volume":"371","author":"Rohatgi","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"ref_186","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1056\/NEJMoa1701329","article-title":"Cardiovascular and Metabolic Effects of ANGPTL3 Antisense Oligonucleotides","volume":"377","author":"Graham","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_187","doi-asserted-by":"crossref","first-page":"e261","DOI":"10.1016\/j.jacl.2023.12.001","article-title":"Hepatic Fat Changes with Antisense Oligonucleotide Therapy Targeting ANGPTL3","volume":"18","author":"Zimerman","year":"2024","journal-title":"J. Clin. Lipidol."},{"key":"ref_188","doi-asserted-by":"crossref","first-page":"1803","DOI":"10.1016\/j.jacc.2025.03.005","article-title":"Effect of ANGPTL3 Inhibition With Solbinsiran in Preclinical and Early Human Studies","volume":"85","author":"Ray","year":"2025","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_189","doi-asserted-by":"crossref","first-page":"913","DOI":"10.1056\/NEJMoa2404147","article-title":"Zodasiran, an RNAi Therapeutic Targeting ANGPTL3, for Mixed Hyperlipidemia","volume":"391","author":"Rosenson","year":"2024","journal-title":"N. Engl. J. Med."},{"key":"ref_190","doi-asserted-by":"crossref","first-page":"1594","DOI":"10.1016\/S0140-6736(25)00507-0","article-title":"Durability and Efficacy of Solbinsiran, a GalNAc-Conjugated siRNA Targeting ANGPTL3, in Adults with Mixed Dyslipidaemia (PROLONG-ANG3): A Double-Blind, Randomised, Placebo-Controlled, Phase 2 Trial","volume":"405","author":"Ray","year":"2025","journal-title":"Lancet"},{"key":"ref_191","doi-asserted-by":"crossref","first-page":"E1420","DOI":"10.1152\/ajpendo.00362.2009","article-title":"Long-Term Fenretinide Treatment Prevents High-Fat Diet-Induced Obesity, Insulin Resistance, and Hepatic Steatosis","volume":"297","author":"Preitner","year":"2009","journal-title":"Am. J. Physiol.-Endocrinol. Metab."},{"key":"ref_192","first-page":"1045","article-title":"Suppression of Retinol-Binding Protein 4 with RNA Oligonucleotide Prevents High-Fat Diet-Induced Metabolic Syndrome and Non-Alcoholic Fatty Liver Disease in Mice","volume":"1811","author":"Tan","year":"2011","journal-title":"Biochim. Et Biophys. Acta (BBA) Mol. Cell Biol. Lipids"},{"key":"ref_193","doi-asserted-by":"crossref","first-page":"1603","DOI":"10.2337\/db14-0970","article-title":"Transthyretin Antisense Oligonucleotides Lower Circulating RBP4 Levels and Improve Insulin Sensitivity in Obese Mice","volume":"64","author":"Zemany","year":"2015","journal-title":"Diabetes"},{"key":"ref_194","doi-asserted-by":"crossref","unstructured":"Bica, I.-C., Stoica, R.A., Salmen, T., Jane\u017e, A., Vol\u010dan\u0161ek, \u0160., Popovic, D., Muzurovic, E., Rizzo, M., and Stoian, A.P. (2023). The Effects of Sodium-Glucose Cotransporter 2-Inhibitors on Steatosis and Fibrosis in Patients with Non-Alcoholic Fatty Liver Disease or Steatohepatitis and Type 2 Diabetes: A Systematic Review of Randomized Controlled Trials. Medicina, 59.","DOI":"10.3390\/medicina59061136"},{"key":"ref_195","doi-asserted-by":"crossref","first-page":"187","DOI":"10.17998\/jlc.2025.06.25","article-title":"Second-Line Antidiabetic Drugs: Friend or Foe of the Liver","volume":"25","author":"Yang","year":"2025","journal-title":"J. Liver Cancer"},{"key":"ref_196","doi-asserted-by":"crossref","first-page":"1565","DOI":"10.1016\/j.cgh.2024.01.032","article-title":"The Emerging Role of Glucagon-Like Peptide-1 Receptor Agonists for the Treatment of Metabolic Dysfunction-Associated Steatohepatitis","volume":"22","author":"Abushamat","year":"2024","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_197","doi-asserted-by":"crossref","first-page":"2461","DOI":"10.1007\/s00125-018-4729-5","article-title":"Management of Hyperglycaemia in Type 2 Diabetes, 2018. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD)","volume":"61","author":"Davies","year":"2018","journal-title":"Diabetologia"},{"key":"ref_198","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1038\/s41574-023-00833-4","article-title":"Metformin: Update on Mechanisms of Action and Repurposing Potential","volume":"19","author":"Foretz","year":"2023","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_199","doi-asserted-by":"crossref","first-page":"1577","DOI":"10.1007\/s00125-017-4342-z","article-title":"The Mechanisms of Action of Metformin","volume":"60","author":"Rena","year":"2017","journal-title":"Diabetologia"},{"key":"ref_200","doi-asserted-by":"crossref","unstructured":"Ruan, G., Wu, F., Shi, D., Sun, H., Wang, F., and Xu, C. (2023). Metformin: Update on Mechanisms of Action on Liver Diseases. Front. Nutr., 10.","DOI":"10.3389\/fnut.2023.1327814"},{"key":"ref_201","doi-asserted-by":"crossref","first-page":"819","DOI":"10.3748\/wjg.v24.i7.819","article-title":"Metformin Attenuates Motility, Contraction, and Fibrogenic Response of Hepatic Stellate Cells in Vivo and in Vitro by Activating AMP-Activated Protein Kinase","volume":"24","author":"Li","year":"2018","journal-title":"World J. Gastroenterol."},{"key":"ref_202","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1038\/ajg.2013.5","article-title":"Anti-Diabetic Medications and the Risk of Hepatocellular Cancer: A Systematic Review and Meta-Analysis","volume":"108","author":"Singh","year":"2013","journal-title":"Am. J. Gastroenterol."},{"key":"ref_203","doi-asserted-by":"crossref","first-page":"465282","DOI":"10.1155\/2012\/465282","article-title":"Metformin Stimulates FGF21 Expression in Primary Hepatocytes","volume":"2012","author":"Nygaard","year":"2012","journal-title":"Exp. Diabetes Res."},{"key":"ref_204","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/j.bbrc.2013.09.026","article-title":"Metformin-Induced Inhibition of the Mitochondrial Respiratory Chain Increases FGF21 Expression via ATF4 Activation","volume":"440","author":"Kim","year":"2013","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_205","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1089\/dia.2015.0261","article-title":"Effect of Metformin on Fibroblast Growth Factor-21 Levels in Patients with Newly Diagnosed Type 2 Diabetes","volume":"18","author":"Fan","year":"2016","journal-title":"Diabetes Technol. Ther."},{"key":"ref_206","doi-asserted-by":"crossref","first-page":"e552","DOI":"10.1210\/clinem\/dgad583","article-title":"Metformin Improves the Prerequisites for FGF21 Signaling in Patients With Type 2 Diabetes","volume":"109","author":"Pedersen","year":"2024","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_207","doi-asserted-by":"crossref","unstructured":"Kolnes, K.J., M\u00f8ller, P.M., Kruse, R., Christensen, M.M.H., Kj\u00f8bsted, R., Hey-Mogensen, M., Andersen, B., Handberg, A., and H\u00f8jlund, K. (2026). Metformin Increases Glycolysis and the Stress-Induced Cytokine GDF15 but Not FGF21 in Humans. Front. Endocrinol., 17.","DOI":"10.3389\/fendo.2026.1797525"},{"key":"ref_208","first-page":"4192940","article-title":"Low-Dose Spironolactone-Pioglitazone-Metformin Normalizes Circulating Fetuin-A Concentrations in Adolescent Girls with Polycystic Ovary Syndrome","volume":"2018","author":"Villarroya","year":"2018","journal-title":"Int. J. Endocrinol."},{"key":"ref_209","doi-asserted-by":"crossref","unstructured":"Hofmann, K., Singer, S., Meyer, A.-C., Theis, S., Hasenburg, A., Brenner, W., and Skala, C. (2025). Fetuin-B as a Biomarker for Metformin Response in Women with Polycystic Ovary Syndrome: A Prospective Study. Front. Med., 12.","DOI":"10.3389\/fmed.2025.1567255"},{"key":"ref_210","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1074\/jbc.M113.479386","article-title":"Metformin Suppresses Expression of the Selenoprotein P Gene via an AMP-Activated Kinase (AMPK)\/FoxO3a Pathway in H4IIEC3 Hepatocytes","volume":"289","author":"Takayama","year":"2014","journal-title":"J. Biol. Chem."},{"key":"ref_211","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1016\/j.bbrc.2009.06.143","article-title":"Attenuation of Hepatic Expression and Secretion of Selenoprotein P by Metformin","volume":"387","author":"Speckmann","year":"2009","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_212","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1111\/jdi.13949","article-title":"Circulating Selenoprotein P Levels Predict Glucose-lowering and Insulinotropic Effects of Metformin, but Not Alogliptin: A Post-hoc Analysis","volume":"14","author":"Takeshita","year":"2023","journal-title":"J. Diabetes Investig."},{"key":"ref_213","doi-asserted-by":"crossref","first-page":"1421","DOI":"10.1111\/jphp.13138","article-title":"AMPK-SIRT1-Independent Inhibition of ANGPTL3 Gene Expression Is a Potential Lipid-Lowering Mechanism of Metformin","volume":"71","author":"Lin","year":"2019","journal-title":"J. Pharm. Pharmacol."},{"key":"ref_214","doi-asserted-by":"crossref","first-page":"852","DOI":"10.1007\/s10620-025-09464-3","article-title":"The Emerging Therapeutic Promise of SGLT2 Inhibitors in Metabolic Dysfunction-Associated Steatotic Liver Disease","volume":"71","author":"Zhang","year":"2026","journal-title":"Dig. Dis. Sci."},{"key":"ref_215","doi-asserted-by":"crossref","unstructured":"Suki, M., Imam, A., Amer, J., Milgrom, Y., Massarwa, M., Hazou, W., Tiram, Y., Perzon, O., Sharif, Y., and Sackran, J. (2025). SGLT2 Inhibitors in MASLD (Metabolic Dysfunction-Associated Steatotic Liver Disease) Associated with Sustained Hepatic Benefits, Besides the Cardiometabolic. Pharmaceuticals, 18.","DOI":"10.3390\/ph18081118"},{"key":"ref_216","doi-asserted-by":"crossref","first-page":"2647","DOI":"10.17305\/bb.2025.12203","article-title":"Effect of SGLT2 Inhibitors on Liver Fat Content: A Meta-Analysis","volume":"25","author":"Ge","year":"2025","journal-title":"Biomol. Biomed."},{"key":"ref_217","doi-asserted-by":"crossref","first-page":"1025","DOI":"10.1007\/s11739-025-03902-w","article-title":"The Effect of SGLT2 Inhibitors on Hepatic Steatosis Detected by MRI-PDFF in Patients with Type 2 Diabetes Mellitus and Metabolic-Associated Steatotic Liver Disease","volume":"20","author":"Amin","year":"2025","journal-title":"Intern. Emerg. Med."},{"key":"ref_218","doi-asserted-by":"crossref","first-page":"1923","DOI":"10.1007\/s00125-018-4675-2","article-title":"Effects of Dapagliflozin and N-3 Carboxylic Acids on Non-Alcoholic Fatty Liver Disease in People with Type 2 Diabetes: A Double-Blind Randomised Placebo-Controlled Study","volume":"61","author":"Eriksson","year":"2018","journal-title":"Diabetologia"},{"key":"ref_219","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1507\/endocrj.EJ19-0013","article-title":"Effects of Sodium-Glucose Cotransporter 2 Inhibitor (Dapagliflozin) on Food Intake and Plasma Fibroblast Growth Factor 21 Levels in Type 2 Diabetes Patients","volume":"66","author":"Kosugi","year":"2019","journal-title":"Endocr. J."},{"key":"ref_220","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1111\/jdi.13179","article-title":"Effects of Dapagliflozin on the Serum Levels of Fibroblast Growth Factor 21 and Myokines and Muscle Mass in Japanese Patients with Type 2 Diabetes: A Randomized, Controlled Trial","volume":"11","author":"Yamakage","year":"2020","journal-title":"J. Diabetes Investig."},{"key":"ref_221","doi-asserted-by":"crossref","first-page":"1576","DOI":"10.1111\/dom.15006","article-title":"Empagliflozin versus Sitagliptin for Ameliorating Intrahepatic Lipid Content and Tissue-specific Insulin Sensitivity in Patients with Early-stage Type 2 Diabetes with Non-alcoholic Fatty Liver Disease: A Prospective Randomized Study","volume":"25","author":"Hiruma","year":"2023","journal-title":"Diabetes Obes. Metab."},{"key":"ref_222","doi-asserted-by":"crossref","unstructured":"Paceana, M.-A., Tartau, L.M., Boboc, I.K.S., Oancea, C.N., Berbecaru-Iovan, A., Foia, C.I., Tartau, C.G., and Bogdan, M. (2026). Diabetes Mellitus and Stroke: Pathophysiological Connections and Therapeutic Potential of GLP-1 and GLP-1\/GIP Receptor Agonists. Pharmaceutics, 18.","DOI":"10.3390\/pharmaceutics18050620"},{"key":"ref_223","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1080\/13543784.2025.2473062","article-title":"The Pleiotropic Effects of Glucagon-like Peptide-1 Receptor Agonists in Patients with Metabolic Dysfunction-Associated Steatohepatitis: A Review for Gastroenterologists","volume":"34","author":"Alkhouri","year":"2025","journal-title":"Expert. Opin. Investig. Drugs"},{"key":"ref_224","doi-asserted-by":"crossref","first-page":"1584","DOI":"10.1002\/hep.23569","article-title":"Glucagon-Like Peptide-1 Receptor Is Present on Human Hepatocytes and Has A Direct Role in Decreasing Hepatic Steatosis in Vitro by Modulating Elements of the Insulin Signaling Pathway","volume":"51","author":"Gupta","year":"2010","journal-title":"Hepatology"},{"key":"ref_225","doi-asserted-by":"crossref","unstructured":"Sharma, S., Mells, J.E., Fu, P.P., Saxena, N.K., and Anania, F.A. (2011). GLP-1 Analogs Reduce Hepatocyte Steatosis and Improve Survival by Enhancing the Unfolded Protein Response and Promoting Macroautophagy. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0025269"},{"key":"ref_226","doi-asserted-by":"crossref","first-page":"468","DOI":"10.1007\/s00018-024-05507-6","article-title":"GLP-1 and GIP Agonism Has No Direct Actions in Human Hepatocytes or Hepatic Stellate Cells","volume":"81","author":"Cabaleiro","year":"2024","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_227","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.jhep.2024.07.006","article-title":"Effect of Pemvidutide, a GLP-1\/Glucagon Dual Receptor Agonist, on MASLD: A Randomized, Double-Blind, Placebo-Controlled Study","volume":"82","author":"Harrison","year":"2025","journal-title":"J. Hepatol."},{"key":"ref_228","doi-asserted-by":"crossref","first-page":"1113","DOI":"10.1056\/NEJMoa2028395","article-title":"A Placebo-Controlled Trial of Subcutaneous Semaglutide in Nonalcoholic Steatohepatitis","volume":"384","author":"Newsome","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_229","doi-asserted-by":"crossref","first-page":"2089","DOI":"10.1056\/NEJMoa2413258","article-title":"Phase 3 Trial of Semaglutide in Metabolic Dysfunction\u2013Associated Steatohepatitis","volume":"392","author":"Sanyal","year":"2025","journal-title":"N. Engl. J. Med."},{"key":"ref_230","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1016\/S0140-6736(15)00803-X","article-title":"Liraglutide Safety and Efficacy in Patients with Non-Alcoholic Steatohepatitis (LEAN): A Multicentre, Double-Blind, Randomised, Placebo-Controlled Phase 2 Study","volume":"387","author":"Armstrong","year":"2016","journal-title":"Lancet"},{"key":"ref_231","doi-asserted-by":"crossref","first-page":"674","DOI":"10.1016\/j.clinre.2020.01.007","article-title":"Effect of Liraglutide Therapy on Serum Fetuin A in Patients with Type 2 Diabetes and Non-Alcoholic Fatty Liver Disease","volume":"44","author":"Zhang","year":"2020","journal-title":"Clin. Res. Hepatol. Gastroenterol."},{"key":"ref_232","doi-asserted-by":"crossref","first-page":"2483435","DOI":"10.1155\/2020\/2483435","article-title":"Elevated Circulating Fetuin-B Levels Are Associated with Insulin Resistance and Reduced by GLP-1RA in Newly Diagnosed PCOS Women","volume":"2020","author":"Mokou","year":"2020","journal-title":"Mediat. Inflamm."},{"key":"ref_233","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/j.peptides.2018.07.001","article-title":"GLP-1 Receptor Agonists Stimulate ANGPTL8 Production through the PI3K\/Akt Pathway in a GLP-1 Receptor-Dependent Manner","volume":"106","author":"Liu","year":"2018","journal-title":"Peptides"},{"key":"ref_234","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.ebiom.2019.02.037","article-title":"Liver-Derived Fibroblast Growth Factor 21 Mediates Effects of Glucagon-like Peptide-1 in Attenuating Hepatic Glucose Output","volume":"41","author":"Liu","year":"2019","journal-title":"EBioMedicine"},{"key":"ref_235","doi-asserted-by":"crossref","first-page":"2154","DOI":"10.1002\/hep.31856","article-title":"Hepatic Fibroblast Growth Factor 21 Is Involved in Mediating Functions of Liraglutide in Mice With Dietary Challenge","volume":"74","author":"Liu","year":"2021","journal-title":"Hepatology"},{"key":"ref_236","doi-asserted-by":"crossref","first-page":"e15620","DOI":"10.14814\/phy2.15620","article-title":"Short-term Semaglutide Treatment Improves FGF21 Responsiveness in Primary Hepatocytes Isolated from High Fat Diet Challenged Mice","volume":"11","author":"Feng","year":"2023","journal-title":"Physiol. Rep."},{"key":"ref_237","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1016\/j.diabet.2016.04.005","article-title":"Exenatide Treatment Decreases Fasting Fibroblast Growth Factor 21 Levels in Patients with Newly Diagnosed Type 2 Diabetes Mellitus","volume":"42","author":"Hu","year":"2016","journal-title":"Diabetes Metab."},{"key":"ref_238","doi-asserted-by":"crossref","first-page":"e23309","DOI":"10.1016\/j.heliyon.2023.e23309","article-title":"Comparison of Changes in Adipokine and Inflammatory Cytokine Levels in Patients with Newly Diagnosed Type 2 Diabetes Treated with Exenatide, Insulin, or Pioglitazone: A Post-Hoc Study of the CONFIDENCE Trial","volume":"10","author":"Yang","year":"2024","journal-title":"Heliyon"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/17\/7917\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T04:42:16Z","timestamp":1789015336000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/17\/7917"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,4]]},"references-count":238,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["ijms27177917"],"URL":"https:\/\/doi.org\/10.3390\/ijms27177917","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,4]]}}}