{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T22:22:59Z","timestamp":1782512579793,"version":"3.54.5"},"reference-count":40,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2021,12,3]],"date-time":"2021-12-03T00:00:00Z","timestamp":1638489600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100007076","name":"Italian Association for Cancer Research","doi-asserted-by":"publisher","award":["IG-20176"],"award-info":[{"award-number":["IG-20176"]}],"id":[{"id":"10.13039\/501100007076","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Fondo Coesione e Sviluppo Regione Autonoma della Sardegna 2017","award":["9417"],"award-info":[{"award-number":["9417"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Activation of thyroid hormone receptor \u03b2 (THR\u03b2) has shown beneficial effects on metabolic alterations, including non-alcoholic fatty liver disease (NAFLD). Here, we investigated the effect of TG68, a novel THR\u03b2 agonist, on fatty liver accumulation and liver injury in mice fed a high-fat diet (HFD). C57BL\/6 mice fed HFD for 17 or 18 weeks, a time when all mice developed massive steatohepatitis, were then given TG68 at a dose of 9.35 or 2.8 mg\/kg for 2 or 3 weeks, respectively. As a reference compound, the same treatment was adopted using equimolar doses of MGL-3196, a selective THR\u03b2 agonist currently in clinical phase III. The results showed that treatment with TG68 led to a reduction in liver weight, hepatic steatosis, serum transaminases, and circulating triglycerides. qRT-PCR analyses demonstrated activation of THR\u03b2, as confirmed by increased mRNA levels of Deiodinase-1 and Malic\u00a0enzyme-1, and changes in lipid metabolism, as revealed by increased expression of Acyl-CoA Oxidase-1 and Carnitine palmitoyltransferase-1. The present results showed that this novel THR\u03b2 agonist exerts an anti-steatogenic effect coupled with amelioration of liver injury in the absence of extra-hepatic side effects, suggesting that TG68 may represent a useful tool for the treatment of NAFLD.<\/jats:p>","DOI":"10.3390\/ijms222313105","type":"journal-article","created":{"date-parts":[[2021,12,5]],"date-time":"2021-12-05T21:01:45Z","timestamp":1638738105000},"page":"13105","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":55,"title":["TG68, a Novel Thyroid Hormone Receptor-\u03b2 Agonist for the Treatment of NAFLD"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4957-9493","authenticated-orcid":false,"given":"Andrea","family":"Caddeo","sequence":"first","affiliation":[{"name":"Unit of Oncology and Molecular Pathology, Department of Biomedical Sciences, University of Cagliari, 09042 Monserrato, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta Anna","family":"Kowalik","sequence":"additional","affiliation":[{"name":"Unit of Oncology and Molecular Pathology, Department of Biomedical Sciences, University of Cagliari, 09042 Monserrato, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"Serra","sequence":"additional","affiliation":[{"name":"Unit of Oncology and Molecular Pathology, Department of Biomedical Sciences, University of Cagliari, 09042 Monserrato, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3608-2031","authenticated-orcid":false,"given":"Massimiliano","family":"Runfola","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Pisa, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Bacci","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Pisa, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0146-6358","authenticated-orcid":false,"given":"Simona","family":"Rapposelli","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Pisa, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6956-9030","authenticated-orcid":false,"given":"Amedeo","family":"Columbano","sequence":"additional","affiliation":[{"name":"Unit of Oncology and Molecular Pathology, Department of Biomedical Sciences, University of Cagliari, 09042 Monserrato, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Perra","sequence":"additional","affiliation":[{"name":"Unit of Oncology and Molecular Pathology, Department of Biomedical Sciences, University of Cagliari, 09042 Monserrato, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,12,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"896","DOI":"10.1016\/j.jhep.2018.05.036","article-title":"Modeling NAFLD Disease Burden in China, France, Germany, Italy, Japan, Spain, United Kingdom, and United States for the Period 2016\u20132030","volume":"69","author":"Estes","year":"2018","journal-title":"J. Hepatol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1002\/hep.28431","article-title":"Global Epidemiology of Nonalcoholic Fatty Liver Disease\u2014Meta-Analytic Assessment of Prevalence, Incidence, and Outcomes","volume":"64","author":"Younossi","year":"2016","journal-title":"Hepatology"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1196","DOI":"10.1016\/j.jhep.2020.02.020","article-title":"Update on NAFLD Genetics: From New Variants to the Clinic","volume":"72","author":"Valenti","year":"2020","journal-title":"J. Hepatol."},{"key":"ref_4","first-page":"434","article-title":"Nonalcoholic Steatohepatitis: Mayo Clinic Experiences with a Hitherto Unnamed Disease","volume":"55","author":"Ludwig","year":"1980","journal-title":"Mayo Clin. Proc."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1038\/s41575-019-0145-7","article-title":"From NASH to HCC: Current Concepts and Future Challenges","volume":"16","author":"Anstee","year":"2019","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1053\/gast.2002.34168","article-title":"Expanding the Natural History of Nonalcoholic Steatohepatitis: From Cryptogenic Cirrhosis to Hepatocellular Carcinoma","volume":"123","author":"Bugianesi","year":"2002","journal-title":"Gastroenterology"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1053\/j.gastro.2005.11.017","article-title":"From Fat to Inflammation","volume":"130","author":"Day","year":"2006","journal-title":"Gastroenterology"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"874","DOI":"10.1097\/COC.0000000000000388","article-title":"Obesity Is Independently Associated with Increased Risk of Hepatocellular Cancer-Related Mortality: A Systematic Review and Meta-Analysis","volume":"41","author":"Gupta","year":"2018","journal-title":"Am. J. Clin. Oncol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1038\/s41587-019-0047-9","article-title":"The New Liver Epidemic","volume":"37","author":"Garber","year":"2019","journal-title":"Nat. Biotechnol."},{"key":"ref_10","first-page":"1097","article-title":"Physiological and Molecular Basis of Thyroid Hormone Action","volume":"81","author":"Yen","year":"2001","journal-title":"Am. Physiol. Soc."},{"key":"ref_11","first-page":"184","article-title":"Thyroid Hormone Receptors: Multiple Forms, Multiple Possibilities","volume":"14","author":"Lazar","year":"1993","journal-title":"Endocr. Rev."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1767","DOI":"10.1210\/me.2002-0009","article-title":"Requirement for Thyroid Hormone Receptor \u03b2 in T3 Regulation of Cholesterol Metabolism in Mice","volume":"16","author":"Gullberg","year":"2002","journal-title":"Mol. Endocrinol."},{"key":"ref_13","first-page":"847","article-title":"The Molecular Basis of Thyroid Hormone Action","volume":"331","author":"Brent","year":"2010","journal-title":"N. Engl. J. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1089\/thy.2000.10.41","article-title":"Functions of Thyroid Hormone Receptors in Mice","volume":"10","author":"Forrest","year":"2009","journal-title":"Thyroid"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"601361","DOI":"10.1155\/2013\/601361","article-title":"Molecular Functions of Thyroid Hormones and Their Clinical Significance in Liver-Related Diseases","volume":"2013","author":"Chi","year":"2013","journal-title":"BioMed Res. Int."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1448","DOI":"10.1530\/EC-18-0499","article-title":"Reduced Expression of Thyroid Hormone Receptor \u03b2 in Human Nonalcoholic Steatohepatitis","volume":"7","author":"Krause","year":"2018","journal-title":"Endocr. Connect."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1002\/hep.27399","article-title":"Local Hypothyroidism Favors the Progression of Preneoplastic Lesions to Hepatocellular Carcinoma in Rats","volume":"61","author":"Frau","year":"2015","journal-title":"Hepatology"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1089\/thy.2007.0248","article-title":"Metabolic Effects of Thyroid Hormone Derivatives","volume":"18","author":"Moreno","year":"2008","journal-title":"Thyroid"},{"key":"ref_19","first-page":"489","article-title":"Selective Activators of Thyroid Hormone Receptors","volume":"13","author":"Webb","year":"2005","journal-title":"Thyroid"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2012","DOI":"10.1016\/S0140-6736(19)32517-6","article-title":"Resmetirom (MGL-3196) for the Treatment of Non-Alcoholic Steatohepatitis: A Multicentre, Randomised, Double-Blind, Placebo-Controlled, Phase 2 Trial","volume":"394","author":"Harrison","year":"2019","journal-title":"Lancet"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1002\/hep4.1657","article-title":"Effects of Resmetirom on Noninvasive Endpoints in a 36-Week Phase 2 Active Treatment Extension Study in Patients With NASH","volume":"5","author":"Harrison","year":"2021","journal-title":"Hepatol. Commun."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"112006","DOI":"10.1016\/j.ejmech.2019.112006","article-title":"Design, Synthesis and Biological Evaluation of Novel TR\u03b2 Selective Agonists Sustained by ADME-Toxicity Analysis","volume":"188","author":"Runfola","year":"2020","journal-title":"Eur. J. Med. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e12808","DOI":"10.1111\/cpr.12808","article-title":"Potential Role of Two Novel Agonists of Thyroid Hormone Receptor-\u03b2 on Liver Regeneration","volume":"53","author":"Perra","year":"2020","journal-title":"Cell Prolif."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"3912","DOI":"10.1021\/jm4019299","article-title":"Discovery of 2-[3,5-Dichloro-4-(5-Isopropyl-6-Oxo-1,6-Dihydropyridazin-3-Yloxy)Phenyl]-3,5-Dioxo-2,3,4,5-Tetrahydro [1, 2, 4]Triazine-6-Carbonitrile (MGL-3196), a Highly Selective Thyroid Hormone Receptor \u03b2 Agonist in Clinical Trials for the Treatment of Dyslipidemia","volume":"57","author":"Kelly","year":"2014","journal-title":"J. Med. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"382","DOI":"10.3389\/fendo.2018.00382","article-title":"Thyroid Hormones, Thyromimetics and Their Metabolites in the Treatment of Liver Disease","volume":"9","author":"Kowalik","year":"2018","journal-title":"Front. Endocrinol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1473","DOI":"10.1007\/BF01308606","article-title":"\u03b1-Smooth-Muscle Actin Expression in Normal and Fibrotic Human Livers","volume":"38","author":"Yamaoka","year":"1993","journal-title":"Dig. Dis. Sci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"975","DOI":"10.1016\/j.jhep.2010.09.020","article-title":"Galectin-3 Ablation Protects Mice from Diet-Induced NASH: A Major Scavenging Role for Galectin-3 in Liver","volume":"54","author":"Iacobini","year":"2011","journal-title":"J. Hepatol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1334","DOI":"10.1053\/j.gastro.2019.11.296","article-title":"Effects of Belapectin, an Inhibitor of Galectin-3, in Patients with Nonalcoholic Steatohepatitis with Cirrhosis and Portal Hypertension","volume":"158","author":"Chalasani","year":"2020","journal-title":"Gastroenterology"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3800","DOI":"10.1074\/jbc.M116.763532","article-title":"Specific Inhibition of Acyl-CoA Oxidase-1 by an Acetylenic Acid Improves Hepatic Lipid and Reactive Oxygen Species (ROS) Metabolism in Rats Fed a High Fat Diet","volume":"292","author":"Zeng","year":"2017","journal-title":"J. Biol. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"550","DOI":"10.2337\/db08-1078","article-title":"Overexpression of Carnitine Palmitoyltransferase-1 in Skeletal Muscle Is Sufficient to Enhance Fatty Acid Oxidation and Improve High-Fat Diet\u2013Induced Insulin Resistance","volume":"58","author":"Bruce","year":"2009","journal-title":"Diabetes"},{"key":"ref_31","first-page":"2330","article-title":"Thyroid Hormone and the Cardiovascular System","volume":"64","author":"Klein","year":"2009","journal-title":"N. Engl. J. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"921","DOI":"10.1007\/s00392-020-01709-7","article-title":"NAFLD and Cardiovascular Diseases: A Clinical Review","volume":"110","author":"Kasper","year":"2021","journal-title":"Clin. Res. Cardiol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"33386","DOI":"10.1038\/srep33386","article-title":"Association of Non-Alcoholic Fatty Liver Disease with Major Adverse Cardiovascular Events: A Systematic Review and Meta-Analysis","volume":"6","author":"Wu","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Weltman, N.Y., Wang, D., Redetzke, R.A., and Gerdes, A.M. (2012). Longstanding Hyperthyroidism Is Associated with Normal or Enhanced Intrinsic Cardiomyocyte Function despite Decline in Global Cardiac Function. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0046655"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1173","DOI":"10.1089\/thy.2018.0664","article-title":"Nonalcoholic Fatty Liver Disease and Hypercholesterolemia: Roles of Thyroid Hormones, Metabolites, and Agonists","volume":"29","author":"Sinha","year":"2019","journal-title":"Thyroid"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"876","DOI":"10.1002\/jgh3.12337","article-title":"Hyperthyroidism and Hepatic Dysfunction: Report of 17 Cases","volume":"4","author":"Wafa","year":"2020","journal-title":"JGH Open"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"922","DOI":"10.1089\/thy.2020.0715","article-title":"Abnormal Liver Blood Tests in Patients with Hyperthyroidism: Systematic Review and Meta-Analysis","volume":"31","author":"Scappaticcio","year":"2021","journal-title":"Thyroid"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2412","DOI":"10.1111\/bph.15427","article-title":"Activation of Thyroid Hormone Receptor-\u03b2 Improved Disease Activity and Metabolism Independent of Body Weight in a Mouse Model of Non-Alcoholic Steatohepatitis and Fibrosis","volume":"178","author":"Kannt","year":"2021","journal-title":"Br. J. Pharmacol."},{"key":"ref_39","unstructured":"Rasband, W.S. (2021, November 30). ImageJ. 1997\u20132018, Available online: https:\/\/imagej.nih.gov\/ij\/."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1038\/nmeth.2089","article-title":"NIH Image to ImageJ: 25 years of image analysis","volume":"9","author":"Schneider","year":"2012","journal-title":"Nat. Methods"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/23\/13105\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:39:34Z","timestamp":1760168374000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/23\/13105"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,3]]},"references-count":40,"journal-issue":{"issue":"23","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["ijms222313105"],"URL":"https:\/\/doi.org\/10.3390\/ijms222313105","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,12,3]]}}}