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However, the duration of these earlier studies was limited to approximately 1 year of treatment, and the ligand used has a higher affinity for the mouse PPAR\u03b1 compared to the human PPAR\u03b1. Thus, the present study examined the effect of long-term administration of a potent, high-affinity human PPAR\u03b1 agonist (GW7647) on hepatocarcinogenesis in wild-type, Ppara-null, or PPARA-humanized mice. In wild-type mice, GW7647 caused hepatic expression of known PPAR\u03b1 target genes, hepatomegaly, hepatic MYC expression, hepatic cytotoxicity, and a high incidence of hepatocarcinogenesis. By contrast, these effects were essentially absent in Ppara-null mice or diminished in PPARA-humanized mice, although hepatocarcinogenesis was observed in both genotypes. Enhanced fatty change (steatosis) was also observed in both Ppara-null and PPARA-humanized mice independent of GW7647. PPARA-humanized mice administered GW7647 also exhibited increased necrosis after 5 weeks of treatment. Results from these studies demonstrate that the mouse PPAR\u03b1 is required for hepatocarcinogenesis induced by GW7647 administered throughout adulthood. Results also indicate that a species difference exists between rodents and human PPAR\u03b1 in the response to ligand activation of PPAR\u03b1. The hepatocarcinogenesis observed in control and treated Ppara-null mice is likely mediated in part by increased hepatic fatty change, whereas the hepatocarcinogenesis observed in PPARA-humanized mice may also be due to enhanced fatty change and cytotoxicity that could be influenced by the minimal activity of the human PPAR\u03b1 in this mouse line on downstream mouse PPAR\u03b1 target genes. The Ppara-null and PPARA-humanized mouse models are valuable tools for examining the mechanisms of PPAR\u03b1-induced hepatocarcinogenesis, but the background level of liver cancer must be controlled for in the design and interpretation of studies that use these mice.<\/jats:p>","DOI":"10.1093\/toxsci\/kfab067","type":"journal-article","created":{"date-parts":[[2021,6,2]],"date-time":"2021-06-02T20:30:27Z","timestamp":1622665827000},"page":"70-80","source":"Crossref","is-referenced-by-count":17,"title":["Diminished Hepatocarcinogenesis by a Potent, High-Affinity Human PPAR\u03b1 Agonist in <i>PPARA<\/i>-Humanized Mice"],"prefix":"10.1093","volume":"183","author":[{"given":"Jennifer E","family":"Foreman","sequence":"first","affiliation":[{"name":"Department of Veterinary and Biomedical Sciences and Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, Pennsylvania 16802, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takayuki","family":"Koga","sequence":"additional","affiliation":[{"name":"Department of Veterinary and Biomedical Sciences and Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, Pennsylvania 16802, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oksana","family":"Kosyk","sequence":"additional","affiliation":[{"name":"Department of Environmental Sciences and Engineering, University of North Carolina, Chapel Hill, North Carolina 27599, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Boo-Hyon","family":"Kang","sequence":"additional","affiliation":[{"name":"Non-clinical Research Institute, Chemon, Yangji-Myeon, Cheoin-Gu, Yongin-Si, Gyeonggi-Do 17162, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyang","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Veterinary and Biomedical Sciences and Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, Pennsylvania 16802, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5047-0962","authenticated-orcid":false,"given":"Samuel M","family":"Cohen","sequence":"additional","affiliation":[{"name":"Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska 68198-3135, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura J","family":"Billy","sequence":"additional","affiliation":[{"name":"Department of Veterinary and Biomedical Sciences and Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, Pennsylvania 16802, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arun K","family":"Sharma","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, The Pennsylvania State University, Hershey, Pennsylvania 17033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shantu","family":"Amin","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, The Pennsylvania State University, Hershey, Pennsylvania 17033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank J","family":"Gonzalez","sequence":"additional","affiliation":[{"name":"Laboratory of Metabolism, National Cancer Institute, Bethesda, Maryland 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivan","family":"Rusyn","sequence":"additional","affiliation":[{"name":"Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, Texas 77843, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey M","family":"Peters","sequence":"additional","affiliation":[{"name":"Department of Veterinary and Biomedical Sciences and Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, Pennsylvania 16802, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,6,3]]},"reference":[{"key":"2021101015230094700_kfab067-B1","doi-asserted-by":"crossref","first-page":"39088","DOI":"10.1074\/jbc.M107073200","article-title":"Peroxisome proliferator-activated receptor-\u03b1 regulates lipid homeostasis, but is not associated with obesity: Studies with congenic mouse lines","volume":"276","author":"Akiyama","year":"2001","journal-title":"J. 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