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

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.