Chimeric mice with hepatocyte-humanized liver as an appropriate model to study human peroxisome proliferator-activated receptor-α.

Abstract

Peroxisome proliferator (PP)-activated receptor-α (PPARα) agonists exhibit species-specific effects on livers of the rodent and human (h), which has been considered to reside in the difference of PPARα 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 β- and ω-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-PPARα-transgenic mice, a hitherto reliable model for studying the regulation of h-PPARα in the h-liver in most respects, except the induction of the peroxisome proliferation. This study indicates the importance of not only h-PPARα 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.

• Authors: Chise Tateno, Toshinobu Yamamoto, Rie Utoh, Chihiro Yamasaki, Yuji Ishida, Yuka Myoken, Ken Oofusa, Miyoko Okada, Naohisa Tsutsui, Katsutoshi Yoshizato
• Journal: Toxicologic pathology (Toxicol Pathol) Vol. 43 Issue 2 Pg. 233-48 (Feb 2015) ISSN: 1533-1601 [Electronic] United States
• PMID: 25107573 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 by The Author(s).

Chemical References

• Hypolipidemic Agents
• PPAR alpha
• Fenofibrate

Topics

• Animals
• Cell Transplantation
• Female
• Fenofibrate (pharmacology)
• Gene Expression (drug effects)
• Hepatocytes (drug effects, metabolism)
• Humans
• Hypolipidemic Agents (pharmacology)
• Liver (drug effects, metabolism)
• Male
• Mice
• Mice, SCID
• PPAR alpha (genetics, metabolism)
• Peroxisomes (drug effects)
• Proteomics
• Signal Transduction (drug effects)