Journal Article Selective peroxisome proliferator-activated receptor-α modulator K-877 efficiently activates the peroxisome proliferator-activated receptor-α pathway and improves lipid metabolism in mice

Takei, Kenta  ,  Han, Song-iee  ,  Murayama, Yuki  ,  Satoh, Aoi  ,  Oikawa, Fusaka  ,  Ohno, Hiroshi  ,  Osaki, Yoshinori  ,  Matsuzaka, Takashi  ,  Sekiya, Motohiro  ,  Iwasaki, Hitoshi  ,  Yatoh, Shigeru  ,  Yahagi, Naoya  ,  Suzuki, Hiroaki  ,  Yamada, Nobuhiro  ,  Nakagawa, Yoshimi  ,  Shimano, Hitoshi

8 ( 4 )  , pp.446 - 452 , 2017-07 , Wiley
ISSN:2040-1116
NCID:AA12488319
Description
Aims/IntroductionPeroxisome 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.
Materials and MethodsTo 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.
ResultsIn 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.
ConclusionsThe 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.
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