{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T15:43:59Z","timestamp":1774280639093,"version":"3.50.1"},"reference-count":31,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2023,9,26]],"date-time":"2023-09-26T00:00:00Z","timestamp":1695686400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100006379","name":"VA Office of Research and Development","doi-asserted-by":"publisher","award":["BX000849"],"award-info":[{"award-number":["BX000849"]}],"id":[{"id":"10.13039\/100006379","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006379","name":"VA Office of Research and Development","doi-asserted-by":"publisher","award":["BX005687"],"award-info":[{"award-number":["BX005687"]}],"id":[{"id":"10.13039\/100006379","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006379","name":"VA Office of Research and Development","doi-asserted-by":"publisher","award":["BX004127"],"award-info":[{"award-number":["BX004127"]}],"id":[{"id":"10.13039\/100006379","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biology"],"abstract":"<jats:p>Peroxisome-proliferator-activated receptor gamma (PPAR\u03b3) is a transcription factor with adipogenic, insulin-sensitizing, and antifibrotic properties. Strong PPAR\u03b3 activators, such as the thiazolidinediones, can induce unwanted effects such as edema, weight gain, and bone loss, and therefore selective modulators of PPAR\u03b3 are in development. We previously reported that one selective PPAR\u03b3 modulator, SR1664, reduced toxin-induced hepatic fibrosis and the activation of hepatic stellate cells (HSCs), the main collagen-producing liver cell in fibrosis. In this study, we used a high fat and high carbohydrate (HFHC) model of hepatic steatosis and fibrosis to determine the effect of SR1664. Mice were placed on a standard chow or HFHC diet for 16 weeks, with SR1664 or control treatment for the final 4 weeks. SR1664 did not alter weight gain or fasting insulin or glucose levels. The size of lipid droplets in the HFHC group was reduced by SR1664, but there was no effect on total liver triglyceride levels. The degree of fibrosis was significantly reduced by SR1664 in mice on the HFHC diet, and this was accompanied by a decrease in activated HSC. In summary, SR1664 improved insulin sensitivity and reduced fibrosis in the HFHC diet, suggesting selective PPAR\u03b3 modulation is effective in obesity-related liver fibrosis.<\/jats:p>","DOI":"10.3390\/biology12101287","type":"journal-article","created":{"date-parts":[[2023,9,27]],"date-time":"2023-09-27T03:04:18Z","timestamp":1695783858000},"page":"1287","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Reduction in Obesity-Related Hepatic Fibrosis by SR1664"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7876-149X","authenticated-orcid":false,"given":"Benita L.","family":"McVicker","sequence":"first","affiliation":[{"name":"Research Service, Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA"},{"name":"Departments of Internal Medicine and Pharmacology & Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ronda L.","family":"Simpson","sequence":"additional","affiliation":[{"name":"Research Service, Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA"},{"name":"Departments of Internal Medicine and Pharmacology & Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Frederick G.","family":"Hamel","sequence":"additional","affiliation":[{"name":"Research Service, Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA"},{"name":"Departments of Internal Medicine and Biochemistry & Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0755-6103","authenticated-orcid":false,"given":"Robert G.","family":"Bennett","sequence":"additional","affiliation":[{"name":"Research Service, Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA"},{"name":"Departments of Internal Medicine and Biochemistry & Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,9,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1038\/nrendo.2016.135","article-title":"PPARs in obesity-induced T2DM, dyslipidaemia and NAFLD","volume":"13","author":"Gross","year":"2017","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"318","DOI":"10.3389\/fphar.2017.00318","article-title":"Novel Anti-fibrotic Therapies","volume":"8","author":"McVicker","year":"2017","journal-title":"Front. Pharmacol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1038\/nature09291","article-title":"Anti-diabetic drugs inhibit obesity-linked phosphorylation of PPARgamma by Cdk5","volume":"466","author":"Choi","year":"2010","journal-title":"Nature"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1038\/nature10383","article-title":"Antidiabetic actions of a non-agonist PPARgamma ligand blocking Cdk5-mediated phosphorylation","volume":"477","author":"Choi","year":"2011","journal-title":"Nature"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1152\/physrev.00013.2007","article-title":"Hepatic Stellate Cells: Protean, Multifunctional, and Enigmatic Cells of the Liver","volume":"88","author":"Friedman","year":"2008","journal-title":"Physiol. Rev."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"S102","DOI":"10.1111\/j.1440-1746.2006.04573.x","article-title":"Anti-adipogenic regulation underlies hepatic stellate cell transdifferentiation","volume":"21","author":"Tsukamoto","year":"2006","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1924","DOI":"10.1053\/gast.2002.33666","article-title":"Antidiabetic thiazolidinediones inhibit collagen synthesis and hepatic stellate cell activation in vivo and in vitro","volume":"122","author":"Galli","year":"2002","journal-title":"Gastroenterology"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1016\/j.bbrc.2004.01.038","article-title":"Pioglitazone prevents hepatic steatosis, fibrosis, and enzyme-altered lesions in rat liver cirrhosis induced by a choline-deficient L-amino acid-defined diet","volume":"315","author":"Kawaguchi","year":"2004","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1006\/bbrc.2002.6385","article-title":"Pioglitazone prevents early-phase hepatic fibrogenesis caused by carbon tetrachloride","volume":"291","author":"Kon","year":"2002","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_10","first-page":"105","article-title":"Peroxisome proliferated-activated receptor gamma ligand, Pioglitazone, does not prevent hepatic fibrosis in mice","volume":"19","author":"Horsmans","year":"2007","journal-title":"Int. J. Mol. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1020","DOI":"10.1136\/gut.2005.079194","article-title":"Limited therapeutic efficacy of pioglitazone on progression of hepatic fibrosis in rats","volume":"55","author":"Leclercq","year":"2006","journal-title":"Gut"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"McVicker, B.L., Hamel, F.G., Simpson, R.L., and Bennett, R.G. (2020). A Selective PPARgamma Modulator Reduces Hepatic Fibrosis. 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Cytochem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"35715","DOI":"10.1074\/jbc.M006577200","article-title":"Peroxisome proliferator-activated receptors and hepatic stellate cell activation","volume":"275","author":"Miyahara","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1053\/gast.2000.9365","article-title":"Ligands of peroxisome proliferator-activated receptor gamma modulate profibrogenic and proinflammatory actions in hepatic stellate cells","volume":"119","author":"Marra","year":"2000","journal-title":"Gastroenterology"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1061","DOI":"10.1007\/s00011-010-0226-0","article-title":"Effectiveness of the PPARgamma agonist, GW570, in liver fibrosis","volume":"59","author":"Yang","year":"2010","journal-title":"Inflamm. Res."},{"key":"ref_19","first-page":"4931","article-title":"Thiazolidinedione treatment inhibits bile duct proliferation and fibrosis in a rat model of chronic cholestasis","volume":"11","author":"Marra","year":"2005","journal-title":"World J. Gastroenterol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"3999","DOI":"10.3748\/wjg.v23.i22.3999","article-title":"Serelaxin increases the antifibrotic action of rosiglitazone in a model of hepatic fibrosis","volume":"23","author":"Bennett","year":"2017","journal-title":"World J. Gastroenterol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1016\/j.jhep.2020.04.025","article-title":"Differential effects of selective- and pan-PPAR agonists on experimental steatohepatitis and hepatic macrophages(\u2606)","volume":"73","author":"Lefere","year":"2020","journal-title":"J. Hepatol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"e0154","DOI":"10.1097\/HC9.0000000000000154","article-title":"Peroxisome proliferator-activated receptor gamma activation ameliorates liver fibrosis-differential action of transcription factor EB and autophagy on hepatocytes and stellate cells","volume":"7","author":"Yum","year":"2023","journal-title":"Hepatol. Commun."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"13595","DOI":"10.1038\/s41598-022-15550-7","article-title":"The effects of the voglibose on non-alcoholic fatty liver disease in mice model","volume":"12","author":"Bae","year":"2022","journal-title":"Sci. Rep."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1007\/s13105-020-00777-7","article-title":"Regulation of peroxisome proliferator-activated receptor-gamma activity affects the hepatic stellate cell activation and the progression of NASH via TGF-beta1\/Smad signaling pathway","volume":"77","author":"Ni","year":"2021","journal-title":"J. Physiol. Biochem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"256","DOI":"10.2337\/diacare.27.1.256","article-title":"Thiazolidinedione use, fluid retention, and congestive heart failure: A consensus statement from the American Heart Association and American Diabetes Association","volume":"27","author":"Nesto","year":"2004","journal-title":"Diabetes Care"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1431","DOI":"10.1016\/j.str.2018.07.007","article-title":"Chemical Crosslinking Mass Spectrometry Reveals the Conformational Landscape of the Activation Helix of PPARgamma; a Model for Ligand-Dependent Antagonism","volume":"26","author":"Zheng","year":"2018","journal-title":"Structure"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"998","DOI":"10.1021\/acsmedchemlett.5b00218","article-title":"Design, Synthesis, and Biological Evaluation of Indole Biphenylcarboxylic Acids as PPARgamma Antagonists","volume":"6","author":"Asteian","year":"2015","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1038\/s41575-023-00807-x","article-title":"Hepatic inflammatory responses in liver fibrosis","volume":"20","author":"Hammerich","year":"2023","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"728","DOI":"10.21037\/atm-20-2948","article-title":"It\u2019s all about the spaces between cells: Role of extracellular matrix in liver fibrosis","volume":"9","author":"Khurana","year":"2021","journal-title":"Ann. Transl. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1002\/jcp.22783","article-title":"PAI-1 in tissue fibrosis","volume":"227","author":"Ghosh","year":"2012","journal-title":"J. Cell. Physiol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e81","DOI":"10.1016\/j.thromres.2011.06.020","article-title":"PPARgamma activation induces acute PAI-1 gene expression in the liver but not in adipose tissues of diabetic model mice","volume":"128","author":"Oishi","year":"2011","journal-title":"Thromb. Res."}],"container-title":["Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2079-7737\/12\/10\/1287\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T20:59:05Z","timestamp":1760129945000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2079-7737\/12\/10\/1287"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,9,26]]},"references-count":31,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2023,10]]}},"alternative-id":["biology12101287"],"URL":"https:\/\/doi.org\/10.3390\/biology12101287","relation":{},"ISSN":["2079-7737"],"issn-type":[{"value":"2079-7737","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,9,26]]}}}