期刊
TOXICOLOGIC PATHOLOGY
卷 43, 期 2, 页码 233-248出版社
SAGE PUBLICATIONS INC
DOI: 10.1177/0192623314544378
关键词
PPAR; humanized mice; human hepatocytes; fenofibrate
资金
- 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
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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