title: 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.affiliation: Yoshizato Project, Cooperative Link of Unique Science and Technology for Economy Revitalization (CLUSTER), Hiroshima Prefectural Institute of Industrial Science and Technology, Higashihiroshima, Japan Liver Research Project Center, Hiroshima University, Hiroshima, Japan PhoenixBio Co., Ltd., Higashihiroshima, Japan chise.mukaidani@phoenixbio.co.jp katsutoshi.yoshizato@phoenixbio.co.jp.
authors.forename: Chise
authors.initials: C
authors.lastname: Tateno
authors.affiliation: Safety Research Laboratory, Mitsubishi Tanabe Pharma Corporation, Kisarazu, Japan.
authors.forename: Toshinobu
authors.initials: T
authors.lastname: Yamamoto
authors.affiliation: Yoshizato Project, Cooperative Link of Unique Science and Technology for Economy Revitalization (CLUSTER), Hiroshima Prefectural Institute of Industrial Science and Technology, Higashihiroshima, Japan Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University, Tokyo, Japan.
authors.forename: Rie
authors.initials: R
authors.lastname: Utoh
authors.affiliation: Yoshizato Project, Cooperative Link of Unique Science and Technology for Economy Revitalization (CLUSTER), Hiroshima Prefectural Institute of Industrial Science and Technology, Higashihiroshima, Japan PhoenixBio Co., Ltd., Higashihiroshima, Japan.
authors.forename: Chihiro
authors.initials: C
authors.lastname: Yamasaki
authors.affiliation: Liver Research Project Center, Hiroshima University, Hiroshima, Japan PhoenixBio Co., Ltd., Higashihiroshima, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Ishida
authors.affiliation: Prophoenix Co., Ltd., Developmental Biology Laboratory, Higashihiroshima, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Myoken
authors.affiliation: Prophoenix Co., Ltd., Developmental Biology Laboratory, Higashihiroshima, Japan Prophoenix Division, Idea Consultants, Osaka, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Oofusa
authors.affiliation: Safety Research Laboratory, Mitsubishi Tanabe Pharma Corporation, Kisarazu, Japan.
authors.forename: Miyoko
authors.initials: M
authors.lastname: Okada
authors.affiliation: Safety Research Laboratory, Mitsubishi Tanabe Pharma Corporation, Kisarazu, Japan.
authors.forename: Naohisa
authors.initials: N
authors.lastname: Tsutsui
authors.affiliation: Yoshizato Project, Cooperative Link of Unique Science and Technology for Economy Revitalization (CLUSTER), Hiroshima Prefectural Institute of Industrial Science and Technology, Higashihiroshima, Japan Liver Research Project Center, Hiroshima University, Hiroshima, Japan PhoenixBio Co., Ltd., Higashihiroshima, Japan Hiroshima University 21st Century COE Program for Advanced Radiation Casualty Medicine, Department of Biological Science, Graduate School of Science, Hiroshima University, Higashihiroshima, Japan chise.mukaidani@phoenixbio.co.jp katsutoshi.yoshizato@phoenixbio.co.jp.
authors.forename: Katsutoshi
authors.initials: K
authors.lastname: Yoshizato
mesh_terms: D000818:Animals; D017690:Cell Transplantation; D005260:Female; D011345:Fenofibrate / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D000960:Hypolipidemic Agents / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D016513:Mice, SCID; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism*; D020675:Peroxisomes / Q000187:drug effects; D040901:Proteomics; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000960:Hypolipidemic Agents; D047493:PPAR alpha; D011345:Fenofibrate
keywords: PPARα; fenofibrate; human hepatocytes; humanized mice