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ToxSci Advance Access published online on August 9, 2007
Toxicological Sciences, doi:10.1093/toxsci/kfm206
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Published by Oxford University Press 2007.

The PPAR{alpha}-humanized Mouse: a Model to Investigate Species Differences in Liver Toxicity Mediated by PPAR{alpha}

Qian Yang, Tomokazu Nagano, Yatrik Shah, Connie Cheung, Shinji Ito and Frank J. Gonzalez

Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892

Correspondence: Frank J. Gonzalez, Building 37, Room 3106, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892. Phone: (301) 496-9067. Fax: (301) 496-8419. E-mail: fjgonz{at}helix.nih.gov

Received July 27, 2007; revision received July 31, 2007; accepted August 1, 2007


  Abstract

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

Key Words: Humanized; PAC; PPAR{alpha}; hepatomegaly; peroxisome proliferators.


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