{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T14:29:26Z","timestamp":1781101766828,"version":"3.54.1"},"reference-count":38,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2024,8,16]],"date-time":"2024-08-16T00:00:00Z","timestamp":1723766400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Acta Physiologica"],"published-print":{"date-parts":[[2024,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background and Aim<\/jats:title><jats:p>Metabolic dysfunction\u2010associated steatohepatitis (MASH) is a metabolic disorder with limited treatment options. The thyroid hormone receptor (THR)\u2010\u03b2 agonist resmetirom\/MGL\u20103196 (MGL) increases liver fat oxidation and has been approved for treating adult MASH. However, over 60% of patients receiving MGL treatment do not achieve MASH resolution. Therefore, we investigated the potential for combination therapy of MGL with the mitochondrial uncoupler BAM15 to improve fatty liver disease outcomes in the GAN mouse model of MASH.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>C57BL\/6J male mice were fed GAN diet for 38\u2009weeks before stratification and randomization to treatments including MGL, BAM15, MGL\u2009+\u2009BAM15, or no drug control for 8\u2009weeks. Treatments were admixed in diet and mice were pair\u2010fed to control for drug intake. Treatment effectiveness was assessed by body weight, body composition, energy expenditure, glucose tolerance, tissue lipid content, and histological analyses.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>MGL\u2009+\u2009BAM15 treatment resulted in better efficacy versus GAN control mice than either monotherapy in the context of energy expenditure, liver fat loss, glucose control, and fatty liver disease activity score. Improvements in ALT, liver mass, and plasma cholesterol were primarily driven by MGL, while improvements in body fat were primarily driven by BAM15. No treatments altered liver fibrosis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>MGL\u2009+\u2009BAM15 treatment had overall better efficacy to improve metabolic outcomes in mice fed GAN diet than either monotherapy alone. These data warrant further investigation into combination therapies of THR\u2010\u03b2 agonists and mitochondrial uncouplers for the potential treatment of disorders related to fatty liver, obesity, and insulin resistance.<\/jats:p><\/jats:sec>","DOI":"10.1111\/apha.14217","type":"journal-article","created":{"date-parts":[[2024,8,17]],"date-time":"2024-08-17T05:23:35Z","timestamp":1723872215000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Beneficial effects of <scp>MGL<\/scp>\u20103196 and <scp>BAM15<\/scp> combination in a mouse model of fatty liver disease"],"prefix":"10.1111","volume":"240","author":[{"given":"Mingyan","family":"Zhou","sequence":"first","affiliation":[{"name":"School of Biotechnology &amp; Biomolecular Sciences, Faculty of Science University of New South Wales  Sydney New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine","family":"Li","sequence":"additional","affiliation":[{"name":"School of Biotechnology &amp; Biomolecular Sciences, Faculty of Science University of New South Wales  Sydney New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frances L.","family":"Byrne","sequence":"additional","affiliation":[{"name":"School of Biotechnology &amp; Biomolecular Sciences, Faculty of Science University of New South Wales  Sydney New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Calum S.","family":"Vancuylenburg","sequence":"additional","affiliation":[{"name":"School of Biotechnology &amp; Biomolecular Sciences, Faculty of Science University of New South Wales  Sydney New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ellen M.","family":"Olzomer","sequence":"additional","affiliation":[{"name":"School of Biotechnology &amp; Biomolecular Sciences, Faculty of Science University of New South Wales  Sydney New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam","family":"Hargreaves","sequence":"additional","affiliation":[{"name":"PathCelerate Ltd  Goostrey UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lindsay E.","family":"Wu","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences, Faculty of Medicine University of New South Wales  Sydney New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas A.","family":"Shackel","sequence":"additional","affiliation":[{"name":"Northern Tasmania, Launceston General Hospital, Tasmania Health Service  Tasmania Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Webster L.","family":"Santos","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Virginia Tech Center for Drug Discovery Virginia Polytechnic Institute and State University  Blacksburg Virginia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0214-3238","authenticated-orcid":false,"given":"Kyle L.","family":"Hoehn","sequence":"additional","affiliation":[{"name":"School of Biotechnology &amp; Biomolecular Sciences, Faculty of Science University of New South Wales  Sydney New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,8,16]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.25762"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2021.08.020"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2005.04.014"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpeds.2012.08.043"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00535-012-0533-z"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2010.09.038"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/oby.23263"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cld.2015.10.001"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.atherosclerosis.2013.07.056"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm4019299"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(19)32517-6"},{"key":"e_1_2_11_13_1","unstructured":"TherapeuticsM.Madrigal Announces Positive Topline Results from the Pivotal Phase 3 MAESTRO\u2010NASH Clinical Trial of Resmetirom for the Treatment of NASH and Liver Fibrosis.2022.https:\/\/ir.madrigalpharma.com\/news\u2010releases\/news\u2010release\u2010details\/madrigal\u2010announces\u2010positive\u2010topline\u2010results\u2010pivotal\u2010phase\u20103"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00030.2013"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.3389\/fmed.2020.00331"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2213-8587(14)70006-3"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.31204"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1002\/pmic.201300376"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbalip.2016.08.011"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.14.193"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.282.17.1659"},{"issue":"4","key":"e_1_2_11_22_1","first-page":"379a","article-title":"Activity of the mitochondrial respiratory chain enzymes is decreased in the liver of patients with nonalcoholic steatohepatitis","volume":"30","author":"Perez\u2010Carrera M","year":"1999","journal-title":"Hepatology"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1053\/gast.2001.23256"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.7b01182"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaa0672"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2020.05.006"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1042\/bse0470053"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmet.2013.11.005"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-16298-2"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmet.2021.101178"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1111\/cts.13235"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.15427"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms24065843"},{"key":"e_1_2_11_34_1","unstructured":"TaubR FrancJ KellyM.MGL\u20103196 a \u03b2\u2010selective thyroid hormone receptor (THR) agonist demonstrates metabolic anti\u2010inflammatory and anti\u2010fibrotic benefits in a Llng\u2010term high fat diet (HFD) mouse NASH model. Poster Presentation Presented at the AASLD Liver Meeting.2017."},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmet.2023.101684"},{"key":"e_1_2_11_36_1","unstructured":"TozziM HansenHH MadsenMR FeigM.Clinical Translatability of the GAN Diet\u2010Induced Obese and Biopsy\u2010Confirmed Mouse Model of NASH.2022.https:\/\/www.gubra.dk\/wp\u2010content\/uploads\/2022\/10\/GAN\u2010DIO\u2010NASH_Preclinical\u2010vs\u2010clinical\u2010data.pdf"},{"key":"e_1_2_11_37_1","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2023.1109615"},{"key":"e_1_2_11_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)64849-5"},{"key":"e_1_2_11_39_1","doi-asserted-by":"publisher","DOI":"10.1038\/s42255-021-00451-2"}],"updated-by":[{"DOI":"10.1111\/apha.14250","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2024,11,12]],"date-time":"2024-11-12T00:00:00Z","timestamp":1731369600000}}],"container-title":["Acta Physiologica"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/apha.14217","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,9,24]],"date-time":"2024-09-24T13:39:11Z","timestamp":1727185151000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/apha.14217"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,8,16]]},"references-count":38,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2024,10]]}},"alternative-id":["10.1111\/apha.14217"],"URL":"https:\/\/doi.org\/10.1111\/apha.14217","archive":["Portico"],"relation":{"correction":[{"id-type":"doi","id":"10.1111\/apha.14250","asserted-by":"object"}]},"ISSN":["1748-1708","1748-1716"],"issn-type":[{"value":"1748-1708","type":"print"},{"value":"1748-1716","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,8,16]]},"assertion":[{"value":"2023-10-22","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-08-04","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-08-16","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e14217"}}