{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T18:09:55Z","timestamp":1789582195243,"version":"build-2803163510"},"reference-count":54,"publisher":"Public Library of Science (PLoS)","issue":"4","license":[{"start":{"date-parts":[[2024,4,25]],"date-time":"2024-04-25T00:00:00Z","timestamp":1714003200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100018262","name":"Intercept Pharmaceuticals","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100018262","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>The nuclear farnesoid X receptor (FXR), a master regulator of bile acid and metabolic homeostasis, is a key target for treatment of nonalcoholic steatohepatitis (NASH). This study compared efficacy of FXR agonists obeticholic acid (OCA) and INT-787 by liver histopathology, plasma biomarkers of liver damage, and hepatic gene expression profiles in the Amylin liver NASH (AMLN) diet\u2013induced and biopsy-confirmed Lep<jats:sup><jats:italic>ob\/ob<\/jats:italic><\/jats:sup> mouse model of NASH. Lep<jats:sup><jats:italic>ob\/ob<\/jats:italic><\/jats:sup> mice were fed the AMLN diet for 12 weeks before liver biopsy and subsequent treatment with vehicle, OCA, or INT-787 for 8 weeks. Hepatic steatosis, inflammation, and fibrosis (liver lipids, galectin-3, and collagen 1a1 [Col1a1], respectively), as well as plasma alanine transaminase (ALT) and aspartate transaminase (AST) levels, were assessed. Hepatic gene expression was assessed in Lep<jats:sup><jats:italic>ob\/ob<\/jats:italic><\/jats:sup> mice that were fed the AMLN diet for 14 weeks then treated with vehicle, OCA, or INT-787 for 2 weeks. INT-787, which is equipotent to OCA but more hydrophilic, significantly reduced liver lipids, galectin-3, and Col1a1 compared with vehicle, and to a greater extent than OCA. INT-787 significantly reduced plasma ALT and AST levels, whereas OCA did not. INT-787 modulated a substantially greater number of genes associated with FXR signaling, lipid metabolism, and stellate cell activation relative to OCA in hepatic tissue. These findings demonstrate greater efficacy of INT-787 treatment compared with OCA in improving liver histopathology, decreasing liver enzyme levels, and enhancing gene regulation, suggesting superior clinical potential of INT-787 for the treatment of NASH and other chronic liver diseases.<\/jats:p>","DOI":"10.1371\/journal.pone.0300809","type":"journal-article","created":{"date-parts":[[2024,4,25]],"date-time":"2024-04-25T17:48:26Z","timestamp":1714067306000},"page":"e0300809","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":8,"title":["Increased hepatoprotective effects of the novel farnesoid X receptor agonist INT-787 versus obeticholic acid in a mouse model of nonalcoholic 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Accessed December 27, 2022. https:\/\/clinicaltrials.gov\/ct2\/show\/NCT02913105."},{"issue":"1","key":"pone.0300809.ref051","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1002\/hep.31205","article-title":"Cilofexor, a nonsteroidal FXR agonist, in patients with noncirrhotic NASH: a phase 2 randomized controlled trial","volume":"72","author":"K Patel","year":"2020","journal-title":"Hepatology"},{"issue":"5","key":"pone.0300809.ref052","doi-asserted-by":"crossref","first-page":"1317","DOI":"10.1016\/j.jhep.2023.07.034","article-title":"FXR agonists in NASH treatment","volume":"79","author":"L Adorini","year":"2023","journal-title":"J Hepatol"},{"issue":"26","key":"pone.0300809.ref053","doi-asserted-by":"crossref","first-page":"2436","DOI":"10.1056\/NEJMra2207599","article-title":"Alcohol-associated hepatitis","volume":"387","author":"R Bataller","year":"2022","journal-title":"N Engl J Med"},{"key":"pone.0300809.ref054","unstructured":"Intercept Pharmaceuticals. FXR effect on severe alcohol-associated hepatitis (FRESH) study. ClinicalTrials.gov identifier: NCT05639543. 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