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Most animal models of NASH lack sufficient validation regarding disease progression and pharmacological treatment. The Gubra\u2010Amylin NASH (GAN) diet\u2010induced obese (DIO) mouse demonstrate clinical translatability with respect to disease etiology and hallmarks of NASH. This study aimed to evaluate disease progression and responsiveness to clinically effective interventions in GAN DIO\u2010NASH mice. Disease phenotyping was performed in male C57BL\/6J mice fed the GAN diet high in fat, fructose, and cholesterol for 28\u201388\u00a0weeks. GAN DIO\u2010NASH mice with biopsy\u2010confirmed NASH and fibrosis received low\u2010caloric dietary intervention, semaglutide (30\u00a0nmol\/kg\/day, s.c.) or lanifibranor (30\u00a0mg\/kg\/day, p.o.) for 8 and 12\u00a0weeks, respectively. Within\u2010subject change in nonalcoholic fatty liver disease (NAFLD) Activity Score (NAS) and fibrosis stage was evaluated using automated deep learning\u2010based image analysis. GAN DIO\u2010NASH mice showed clear and reproducible progression in NASH, fibrosis stage, and tumor burden with high incidence of hepatocellular carcinoma. Consistent with clinical trial outcomes, semaglutide and lanifibranor improved NAS, whereas only lanifibranor induced regression in the fibrosis stage. Dietary intervention also demonstrated substantial benefits on metabolic outcomes and liver histology. Differential therapeutic efficacy of semaglutide, lanifibranor, and dietary intervention was supported by quantitative histology, RNA sequencing, and blood\/liver biochemistry. In conclusion, the GAN DIO\u2010NASH mouse model recapitulates various histological stages of NASH and faithfully reproduces histological efficacy profiles of compounds in advanced clinical development for NASH. Collectively, these features highlight the utility of GAN DIO\u2010NASH mice in preclinical drug development.<\/jats:p>","DOI":"10.1111\/cts.13235","type":"journal-article","created":{"date-parts":[[2022,2,10]],"date-time":"2022-02-10T15:44:02Z","timestamp":1644507842000},"page":"1167-1186","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":81,"title":["Hepatoprotective effects of semaglutide, lanifibranor and dietary intervention in the GAN diet\u2010induced obese and biopsy\u2010confirmed mouse model of NASH"],"prefix":"10.1111","volume":"15","author":[{"given":"Mathias B.","family":"M\u00f8llerh\u00f8j","sequence":"first","affiliation":[{"name":"Gubra  H\u00f8rsholm Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanne S.","family":"Veidal","sequence":"additional","affiliation":[{"name":"Gubra  H\u00f8rsholm Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kirstine T\u00f8lb\u00f8l","family":"Thrane","sequence":"additional","affiliation":[{"name":"Gubra  H\u00f8rsholm Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denise","family":"Or\u00f3","sequence":"additional","affiliation":[{"name":"Gubra  H\u00f8rsholm Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agnete","family":"Overgaard","sequence":"additional","affiliation":[{"name":"Gubra  H\u00f8rsholm Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Casper Gravesen","family":"Salinas","sequence":"additional","affiliation":[{"name":"Gubra  H\u00f8rsholm Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin R\u00f8nn","family":"Madsen","sequence":"additional","affiliation":[{"name":"Gubra  H\u00f8rsholm Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Larissa","family":"Pfisterer","sequence":"additional","affiliation":[{"name":"Boehringer\u2010Ingelheim Pharma GmbH &amp; Co. 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