title: Selective peroxisome proliferator-activated receptor-α modulator K-877 efficiently activates the peroxisome proliferator-activated receptor-α pathway and improves lipid metabolism in mice.
abstract: OBJECTIVE
  Peroxisome proliferator-activated receptor-α (PPARα) is a therapeutic target for hyperlipidemia. K-877 is a new selective PPARα modulator (SPPARMα) that activates PPARα transcriptional activity. The aim of the present study was to assess the effects of K-877 on lipid metabolism in vitro and in vivo compared with those of classical PPARα agonists.
  
  
  METHODS
  To compare the effects of K-877 on PPARα transcriptional activity with those of the classical PPARα agonists Wy14643 (Wy) and fenofibrate (Feno), the cell-based PPARα transactivation luciferase assay was carried out. WT and Ppara-/-mice were fed with a moderate-fat (MF) diet for 6 days, and methionine-choline-deficient (MCD) diet for 4 weeks containing Feno or K-877.
  
  
  RESULTS
  In luciferase assays, K-877 activated PPARα transcriptional activity more efficiently than the classical PPARα agonists Feno and Wy. After being fed MF diet containing 0.001% K-877 or 0.2% Feno for 6 days, mice in the K-877 group showed significant increases in the expression of Ppara and its target genes, leading to marked reductions in plasma triglyceride levels compared with those observed in Feno-treated animals. These K-877 effects were blunted in Ppara-/-mice, confirming that K-877 activates PPARα. In further experiments, K-877 (0.00025%) and Feno (0.1%) equally improved the pathology of MCD diet-induced non-alcoholic fatty liver disease, with increased expression of hepatic fatty acid oxidation genes.
  
  
  CONCLUSIONS
  The present data show that K-877 is an attractive PPARα-modulating drug and can efficiently reduce plasma triglyceride levels, thereby alleviating the dysregulation of lipid metabolism.
authors.affiliation: Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.
authors.forename: Kenta
authors.initials: K
authors.lastname: Takei
authors.affiliation: Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.
authors.forename: Song-Iee
authors.initials: SI
authors.lastname: Han
authors.affiliation: Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Murayama
authors.affiliation: Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.
authors.forename: Aoi
authors.initials: A
authors.lastname: Satoh
authors.affiliation: Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.
authors.forename: Fusaka
authors.initials: F
authors.lastname: Oikawa
authors.affiliation: Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ohno
authors.affiliation: Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Osaki
authors.affiliation: Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Matsuzaka
authors.affiliation: Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.
authors.forename: Motohiro
authors.initials: M
authors.lastname: Sekiya
authors.affiliation: Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Iwasaki
authors.affiliation: Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Yatoh
authors.affiliation: Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.
authors.forename: Naoya
authors.initials: N
authors.lastname: Yahagi
authors.affiliation: Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Suzuki
authors.affiliation: Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Yamada
authors.affiliation: Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.|International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Ibaraki, Japan.
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Nakagawa
authors.affiliation: Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.|International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Ibaraki, Japan.|Life Science Center, Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, Tsukuba, Ibaraki, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Shimano
mesh_terms: D000818:Animals; D001583:Benzoxazoles / Q000494:pharmacology*; D002087:Butyrates / Q000494:pharmacology*; D002460:Cell Line; D004353:Drug Evaluation, Preclinical; D011345:Fenofibrate / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects*; D000960:Hypolipidemic Agents / Q000494:pharmacology; D050356:Lipid Metabolism / Q000187:drug effects*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D047493:PPAR alpha / Q000819:agonists*; D011743:Pyrimidines / Q000494:pharmacology; D000071717:X-Box Binding Protein 1 / Q000378:metabolism
chemical_list: D001583:Benzoxazoles; D002087:Butyrates; D000960:Hypolipidemic Agents; C000603947:K-877 compound; D047493:PPAR alpha; D011743:Pyrimidines; D000071717:X-Box Binding Protein 1; C000605544:Xbp1 protein, mouse; C006253:pirinixic acid; D011345:Fenofibrate
keywords: Lipid metabolism; Peroxisome proliferator-activated receptor-α; Selective peroxisome proliferator-activated receptor-α modulator