| First Author | Foreman JE | Year | 2021 |
| Journal | Toxicol Sci | Volume | 183 |
| Issue | 1 | Pages | 70-80 |
| PubMed ID | 34081128 | Mgi Jnum | J:331739 |
| Mgi Id | MGI:7398355 | Doi | 10.1093/toxsci/kfab067 |
| Citation | Foreman JE, et al. (2021) Diminished Hepatocarcinogenesis by a Potent, High-Affinity Human PPARalpha Agonist in PPARA-Humanized Mice. Toxicol Sci 183(1):70-80 |
| abstractText | Ppara-null and PPARA-humanized mice are refractory to hepatocarcinogenesis caused by the peroxisome proliferator-activated receptor-alpha (PPARalpha) agonist Wy-14,643. 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 PPARalpha compared to the human PPARalpha. Thus, the present study examined the effect of long-term administration of a potent, high-affinity human PPARalpha agonist (GW7647) on hepatocarcinogenesis in wild-type, Ppara-null, or PPARA-humanized mice. In wild-type mice, GW7647 caused hepatic expression of known PPARalpha 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 PPARalpha is required for hepatocarcinogenesis induced by GW7647 administered throughout adulthood. Results also indicate that a species difference exists between rodents and human PPARalpha in the response to ligand activation of PPARalpha. 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 PPARalpha in this mouse line on downstream mouse PPARalpha target genes. The Ppara-null and PPARA-humanized mouse models are valuable tools for examining the mechanisms of PPARalpha-induced hepatocarcinogenesis, but the background level of liver cancer must be controlled for in the design and interpretation of studies that use these mice. |
