The PPARa-Humanized Mouse: A Model to Investigate Species Differences in Liver Toxicity Mediated by PPARa

To determine the impact of the species difference between rodents and humans in response to peroxisome proliferators (PPs) mediated by peroxisome proliferator–activated receptor (PPAR)a, PPARa-humanized transgenic mice were generated using a P1 phage artificial chromosome (PAC) genomic clone bred onto a ppara-null mouse background, designated hPPARa. In hPPARa mice, the human PPARa gene is expressed in tissues with high fatty acid catabolism and induced upon fasting, similar to mouse PPARa in wild-type (Wt) mice. Upon treatment with the PP fenofibrate, hPPARa mice exhibited responses similar to Wt mice, including peroxisome proliferation, lowering of serum triglycerides, and induction of PPARa target genes encoding enzymes involved in fatty acid metabolism in liver, kidney, and heart, suggesting that human PPARa (hPPARa) functions in the same manner as mouse PPARa in regulating fatty acid metabolism and lowering serum triglycerides. However, in contrast to Wt mice, treatment of hPPARa mice with fenofibrate did not cause significant hepatomegaly and hepatocyte proliferation, thus indicating that the mechanisms by which PPARa affects lipid metabolism are distinct from the hepatocyte proliferation response, the latter of which is only induced by mouse PPARa. In addition, a differential regulation of several genes, including the oncogenic let-7C miRNA by PPs, was observed between Wt and hPPARa mice that may contribute to the inherent difference between mouse and human PPARa in activation of hepatocellular proliferation. The hPPARa mouse model provides an in vivo platform to investigate the species difference mediated by PPARa and an ideal model for human risk assessment PPs exposure.