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

Abstract

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