| First Author | Yang Q | Year | 2008 |
| Journal | Toxicol Sci | Volume | 101 |
| Issue | 1 | Pages | 132-9 |
| PubMed ID | 17690133 | Mgi Jnum | J:129053 |
| Mgi Id | MGI:3768588 | Doi | 10.1093/toxsci/kfm206 |
| Citation | Yang Q, et al. (2008) The PPAR{alpha}-Humanized Mouse: A Model to Investigate Species Differences in Liver Toxicity Mediated by PPAR{alpha}. Toxicol Sci 101(1):132-9 |
| abstractText | 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)alpha, PPARalpha-humanized transgenic mice were generated using a P1 phage artificial chromosome (PAC) genomic clone bred onto a pparalpha-null mouse background, designated hPPARalpha(PAC). In hPPARalpha(PAC) mice, the human PPARalpha gene is expressed in tissues with high fatty acid catabolism and induced upon fasting, similar to mouse PPARalpha in wild-type (Wt) mice. Upon treatment with the PP fenofibrate, hPPARalpha(PAC) mice exhibited responses similar to Wt mice, including peroxisome proliferation, lowering of serum triglycerides, and induction of PPARalpha target genes encoding enzymes involved in fatty acid metabolism in liver, kidney, and heart, suggesting that human PPARalpha (hPPARalpha) functions in the same manner as mouse PPARalpha in regulating fatty acid metabolism and lowering serum triglycerides. However, in contrast to Wt mice, treatment of hPPARalpha(PAC) mice with fenofibrate did not cause significant hepatomegaly and hepatocyte proliferation, thus indicating that the mechanisms by which PPARalpha affects lipid metabolism are distinct from the hepatocyte proliferation response, the latter of which is only induced by mouse PPARalpha. In addition, a differential regulation of several genes, including the oncogenic let-7C miRNA by PPs, was observed between Wt and hPPARalpha(PAC) mice that may contribute to the inherent difference between mouse and human PPARalpha in activation of hepatocellular proliferation. The hPPARalpha(PAC) mouse model provides an in vivo platform to investigate the species difference mediated by PPARalpha and an ideal model for human risk assessment PPs exposure. |
