{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T00:15:03Z","timestamp":1790036103447,"version":"4.0.1"},"reference-count":53,"publisher":"Public Library of Science (PLoS)","issue":"12","license":[{"start":{"date-parts":[[2020,12,11]],"date-time":"2020-12-11T00:00:00Z","timestamp":1607644800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>\n                    Thyroid hormones are important modulators of metabolic activity in mammals and alter cholesterol and fatty acid levels through activation of the nuclear thyroid hormone receptor (THR). Currently, there are several THR\u03b2 agonists in clinical trials for the treatment of non-alcoholic steatohepatitis (NASH) that have demonstrated the potential to reduce liver fat and restore liver function. In this study, we tested three THR\u03b2-agonism-based NASH treatment candidates, GC-1 (sobetirome), MGL-3196 (resmetirom), and VK2809, and compared their selectivity for THR\u03b2 and their ability to modulate the expression of genes specific to cholesterol and fatty acid biosynthesis and metabolism\n                    <jats:italic>in vitro<\/jats:italic>\n                    using human hepatic cells and\n                    <jats:italic>in vivo<\/jats:italic>\n                    using a rat model. Treatment with GC-1 upregulated the transcription of\n                    <jats:italic>CPT1A<\/jats:italic>\n                    in the human hepatocyte-derived Huh-7 cell line with a dose-response comparable to that of the native THR ligand, triiodothyronine (T3). VK2809A (active parent of VK2809), MGL-3196, and VK2809 were approximately 30-fold, 1,000-fold, and 2,000-fold less potent than T3, respectively. Additionally, these relative potencies were confirmed by quantification of other direct gene targets of THR, namely,\n                    <jats:italic>ANGPTL4<\/jats:italic>\n                    and\n                    <jats:italic>DIO1<\/jats:italic>\n                    . In primary human hepatocytes, potencies were conserved for every compound except for VK2809, which showed significantly increased potency that was comparable to that of its active counterpart, VK2809A. In high-fat diet fed rats, a single dose of T3 significantly reduced total cholesterol levels and concurrently increased liver\n                    <jats:italic>Dio1<\/jats:italic>\n                    and\n                    <jats:italic>Me1<\/jats:italic>\n                    RNA expression. MGL-3196 treatment resulted in concentration-dependent decreases in total and low-density lipoprotein cholesterol with corresponding increases in liver gene expression, but the compound was significantly less potent than T3. In conclusion, we have implemented a strategy to rank the efficacy of THR\u03b2 agonists by quantifying changes in the transcription of genes that lead to metabolic alterations, an effect that is directly downstream of THR binding and activation.\n                  <\/jats:p>","DOI":"10.1371\/journal.pone.0240338","type":"journal-article","created":{"date-parts":[[2020,12,11]],"date-time":"2020-12-11T13:45:48Z","timestamp":1607694348000},"page":"e0240338","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":45,"title":["Regulation of gene transcription by thyroid hormone receptor \u03b2 agonists in clinical development for the treatment of non-alcoholic steatohepatitis (NASH)"],"prefix":"10.1371","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0600-8778","authenticated-orcid":true,"given":"Xuan 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