Journal
TOXICOLOGIC PATHOLOGY
Volume 43, Issue 2, Pages 233-248Publisher
SAGE PUBLICATIONS INC
DOI: 10.1177/0192623314544378
Keywords
PPAR; humanized mice; human hepatocytes; fenofibrate
Categories
Funding
- Cooperative Link of Unique Science and Technology for Economy Revitalization (CLUSTER), Promotion of Science and Technology in Regional Areas, Ministry of Education, Culture, Sports, Science and Technology, Japan
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Peroxisome proliferator (PP)-activated receptor- (PPAR) agonists exhibit species-specific effects on livers of the rodent and human (h), which has been considered to reside in the difference of PPAR 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 - 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-PPAR-transgenic mice, a hitherto reliable model for studying the regulation of h-PPAR in the h-liver in most respects, except the induction of the peroxisome proliferation. This study indicates the importance of not only h-PPAR 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.
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