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- 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.
- Authors
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
- Abstract
Aims/Introduction 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. Materials and 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.
- Subjects
HYPERLIPIDEMIA treatment; PGC-1 protein; TARGETED drug delivery; PEROXISOME proliferator-activated receptors; LIPID metabolism; LABORATORY mice
- Publication
Journal of Diabetes Investigation, 2017, Vol 8, Issue 4, p446
- ISSN
2040-1116
- Publication type
Article
- DOI
10.1111/jdi.12621