Species Differences between Mouse and Human PPARα in Modulating the Hepatocarcinogenic Effects of Perinatal Exposure to a High-Affinity Human PPARα Agonist in Mice

Abstract

Abstract Evidence suggests that species differences exist between rodents and humans in their biological responses to ligand activation of PPARα. Moreover, neonatal/postnatal rodents may be more sensitive to the effects of activating PPARα. Thus, the present studies examined the effects of chronic ligand activation of PPARα initiated during early neonatal development and continued into adulthood on hepatocarcinogenesis in mice. Wild-type, Ppara-null, or PPARA-humanized mice were administered a potent, high-affinity human PPARα agonist GW7647, and cohorts of mice were examined over time. Activation of PPARα with GW7647 increased expression of known PPARα target genes in liver and was associated with hepatomegaly, increased hepatic cytotoxicity and necrosis, increased expression of hepatic MYC, and a high incidence of hepatocarcinogenesis in wild-type mice. These effects did not occur or were largely diminished in Ppara-null and PPARA-humanized mice, although background levels of hepatocarcinogenesis were also noted in both Ppara-null and PPARA-humanized mice. More fatty change (steatosis) was also observed in both Ppara-null and PPARA-humanized mice independent of GW7647 administration. Results from these studies indicate that the mouse PPARα is required to mediate hepatocarcinogenesis induced by GW7647 in mice and that activation of the human PPARα with GW7647 in PPARA-humanized mice are diminished compared with wild-type mice. Ppara-null and PPARA-humanized mice are valuable tools for examining species differences in the mechanisms of PPARα-induced hepatocarcinogenesis, but background levels of liver cancer observed in aged Ppara-null and PPARA-humanized mice must be considered when interpreting results from studies that use these models. These results also demonstrate that early life exposure to a potent human PPARα agonist does not enhance sensitivity to hepatocarcinogenesis.