Chimeric Mice with Hepatocyte-humanized Liver as an Appropriate Model to Study Human Peroxisome Proliferator–activated Receptor-α

Peroxisome proliferator (PP)–activated receptor-a (PPARa) agonists exhibit species-specific effects on livers of the rodent and human (h), which has been considered to reside in the difference of PPARa gene structures. However, the contribution of h-hepatocytes (heps) to the species-specificity remains to be clarified. In this study, the effects of fenofibrate were investigated using a hepatocyte-humanized chimeric mouse (m) model whose livers were replaced with h-heps at >70%. Fenofibrate induced hepatocellular hypertrophy, cell proliferation, and peroxisome proliferation in livers of severe combined immunodeficiency (SCID) mice, but not in the h-hep of chimeric mouse livers. Fenofibrate increased the expression of the enzymes of b- and !-hydroxylation and deoxygenation of lipids at both gene and protein levels in SCID mouse livers, but not in the h-heps of chimeric mouse livers, supporting the studies with h-PPARa-transgenic mice, a hitherto reliable model for studying the regulation of h-PPARa in the hliver in most respects, except the induction of the peroxisome proliferation. This study indicates the importance of not only h-PPARa gene but also h-heps themselves to correctly predict effects of fibrates on h-livers, and, therefore, suggests that the chimeric mouse is a currently available, consistent, and reliable model to obtain pharmaceutical data concerning the effects of fibrates on h-livers.