title: The peroxisome proliferator-activated receptor (PPAR) α agonist fenofibrate suppresses chemically induced lung alveolar proliferative lesions in male obese hyperlipidemic mice.
abstract: Activation of peroxisome proliferator-activated receptor (PPAR) α disrupts growth-related activities in a variety of human cancers. This study was designed to determine whether fenofibrate, a PPARα agonist, can suppress 4-nitroquinoline 1-oxide (4-NQO)-induced proliferative lesions in the lung of obese hyperlipidemic mice. Male Tsumura Suzuki Obese Diabetic mice were subcutaneously injected with 4-NQO to induce lung proliferative lesions, including adenocarcinomas. They were then fed a diet containing 0.01% or 0.05% fenofibrate for 29 weeks, starting 1 week after 4-NQO administration. At week 30, the incidence and multiplicity (number of lesions/mouse) of pulmonary proliferative lesions were lower in mice treated with 4-NQO and both doses of fenofibrate compared with those in mice treated with 4-NQO alone. The incidence and multiplicity of lesions were significantly lower in mice treated with 4-NQO and 0.05% fenofibrate compared with those in mice treated with 4-NQO alone (p<0.05). Both doses of fenofibrate significantly reduced the proliferative activity of the lesions in 4-NQO-treated mice (p<0.05). Fenofibrate also significantly reduced the serum insulin and insulin-like growth factor (IGF)-1 levels, and decreased the immunohistochemical expression of IGF-1 receptor (IGF-1R), phosphorylated Akt, and phosphorylated Erk1/2 in lung adenocarcinomas. Our results indicate that fenofibrate can prevent the development of 4-NQO-induced proliferative lesions in the lung by modulating the insulin-IGF axis.
authors.affiliation: Department of Experimental Pathology and Tumor Biology, Graduate School of Medical Sciences, Nagoya City University, Nagoya 467-8601, Japan. tkuno@med.nagoya-cu.ac.jp.
authors.forename: Toshiya
authors.initials: T
authors.lastname: Kuno
authors.affiliation: Department of Tumor Pathology, Graduate School of Medicine, Gifu University, Gifu 501-1194, Japan. k-hata-sun@hhc.eisai.co.jp.
authors.forename: Kazuya
authors.initials: K
authors.lastname: Hata
authors.affiliation: Department of Tumor Pathology, Graduate School of Medicine, Gifu University, Gifu 501-1194, Japan. sw20.3s-gte@hotmail.co.jp.
authors.forename: Manabu
authors.initials: M
authors.lastname: Takamatsu
authors.affiliation: Department of Tumor Pathology, Graduate School of Medicine, Gifu University, Gifu 501-1194, Japan. ahara@gifu-u.ac.jp.
authors.forename: Akira
authors.initials: A
authors.lastname: Hara
authors.affiliation: Department of Pathology, Osaka Medical College, Osaka 569-8686, Japan. hirose@art.osaka-med.ac.jp.
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Hirose
authors.affiliation: Department of Experimental Pathology and Tumor Biology, Graduate School of Medical Sciences, Nagoya City University, Nagoya 467-8601, Japan. sattak@med.nagoya-cu.ac.jp.
authors.forename: Satoru
authors.initials: S
authors.lastname: Takahashi
authors.affiliation: Onco-Pathology, Department of Pathology and Host-Defenses, Faculty of Medicine, Kagawa University, Kagawa 761-0793, Japan. imaida@med.kagawa-u.ac.jp.
authors.forename: Katsumi
authors.initials: K
authors.lastname: Imaida
authors.affiliation: Department of Tumor Pathology, Graduate School of Medicine, Gifu University, Gifu 501-1194, Japan. takutt@toukaisaibou.co.jp.
authors.forename: Takuji
authors.initials: T
authors.lastname: Tanaka
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D011345:Fenofibrate / Q000494:pharmacology* / Q000627:therapeutic use; D006949:Hyperlipidemias / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D000960:Hypolipidemic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D007328:Insulin / Q000097:blood; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008820:Mice, Obese; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D047493:PPAR alpha / Q000819:agonists* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D017526:Receptor, IGF Type 1 / Q000378:metabolism
chemical_list: D000960:Hypolipidemic Agents; D007328:Insulin; D047493:PPAR alpha; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D011345:Fenofibrate