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

• Published in: Journal of diabetes investigation 2017-07, Vol.8 (4), p.446-452
• Main 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
• Format: Article
• Language: English
• Subjects: Animals; Benzoxazoles - pharmacology; Butyrates - pharmacology; Cell Line; Choline; Drug Evaluation, Preclinical; Fatty liver; Fenofibrate; Fenofibrate - pharmacology; Gene Expression - drug effects; Hyperlipidemia; Hypolipidemic Agents - pharmacology; Lipid metabolism; Lipid Metabolism - drug effects; Lipids; Liver - drug effects; Liver - metabolism; Liver diseases; Male; Metabolism; Methionine; Mice, Inbred C57BL; Original; Oxidation; Peroxisome proliferator-activated receptors; Peroxisome proliferator‐activated receptor‐α; PPAR alpha - agonists; Pyrimidines - pharmacology; Rodents; Selective peroxisome proliferator‐activated receptor‐α modulator; Transcription; X-Box Binding Protein 1 - metabolism
• ISSN: 2040-1116; 2040-1124
• DOI: 10.1111/jdi.12621

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. K‐877 activates PPARα transcriptional activity more efficiently than Feno and Wy14643 K‐877 efficiently increases Fgf21 expression in vitro and in vivo