{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,18]],"date-time":"2026-10-18T02:29:38Z","timestamp":1792290578648,"version":"4.4.0"},"reference-count":40,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2021,4,6]],"date-time":"2021-04-06T00:00:00Z","timestamp":1617667200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2021,6]]},"abstract":"<jats:sec><jats:title>Background and Purpose<\/jats:title><jats:p>Activation of hepatic thyroid hormone receptor \u03b2 (THR\u2010\u03b2) is associated with systemic lipid lowering, increased bile acid synthesis, and fat oxidation. In patients with non\u2010alcoholic steatohepatitis (NASH), treatment with THR\u2010\u03b2 agonists decreased hepatic steatosis and circulating lipids, and induced resolution of NASH. We chose resmetirom (MGL\u20103196), a liver\u2010directed, selective THR\u2010\u03b2 agonist, as a prototype to investigate the effects of THR\u2010\u03b2 activation in mice with diet\u2010induced obesity (DIO) and biopsy\u2010confirmed advanced NASH with fibrosis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>C57Bl\/6J mice were fed a diet high in fat, fructose, and cholesterol for 34\u2009weeks, and only biopsy\u2010confirmed DIO\u2010NASH mice with fibrosis were included. Resmetirom was administered at a daily dose of 3\u2009mg\u00b7kg<jats:sup>\u22121<\/jats:sup> p.o., for 8\u2009weeks. Systemic and hepatic metabolic parameters, histological non\u2010alcoholic fatty liver disease (NAFLD) activity and fibrosis scores, and liver RNA expression profiles were determined to assess the effect of THR\u2010\u03b2 activation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>Treatment with resmetirom did not influence body weight but led to significant reduction in liver weight, hepatic steatosis, plasma alanine aminotransferase activity, liver and plasma cholesterol, and blood glucose. These metabolic effects translated into significant improvement in NAFLD activity score. Moreover, a lower content of \u03b1\u2010smooth muscle actin and down\u2010regulation of genes involved in fibrogenesis indicated a decrease in hepatic fibrosis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion and Implications<\/jats:title><jats:p>Our model robustly reflected clinical observations of body weight\u2010independent improvements in systemic and hepatic metabolism including anti\u2010steatotic activity.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.15427","type":"journal-article","created":{"date-parts":[[2021,3,3]],"date-time":"2021-03-03T09:57:07Z","timestamp":1614765427000},"page":"2412-2423","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":137,"title":["Activation of thyroid hormone receptor\u2010\u03b2 improved disease activity and metabolism independent of body weight in a mouse model of non\u2010alcoholic steatohepatitis and fibrosis"],"prefix":"10.1111","volume":"178","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5197-2286","authenticated-orcid":false,"given":"Aimo","family":"Kannt","sequence":"first","affiliation":[{"name":"Diabetes Research Sanofi Research and Development  Frankfurt Germany"},{"name":"Institute of Pharmacology Goethe University  Frankfurt Germany"},{"name":"Department of Drug Discovery Fraunhofer Institute for Translational Medicine and Pharmacology ITMP  Frankfurt Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paulus","family":"Wohlfart","sequence":"additional","affiliation":[{"name":"Diabetes Research Sanofi Research and Development  Frankfurt Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas Nygaard","family":"Madsen","sequence":"additional","affiliation":[{"name":"NASH CRO Gubra  H\u00f8rsholm Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanne Skovg\u00e5rd","family":"Veidal","sequence":"additional","affiliation":[{"name":"NASH CRO Gubra  H\u00f8rsholm Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Feigh","sequence":"additional","affiliation":[{"name":"NASH CRO Gubra  H\u00f8rsholm Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dieter","family":"Schmoll","sequence":"additional","affiliation":[{"name":"Diabetes Research Sanofi Research and Development  Frankfurt Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,4,6]]},"reference":[{"issue":"1","key":"e_1_2_12_2_1","first-page":"S229","article-title":"The Concise Guide to PHARMACOLOGY 2019\/20: Nuclear hormone receptors","volume":"176","author":"Alexander S. 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