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-alpha (PPAR alpha) is a therapeutic target for hyperlipidemia. K-877 is a new selective PPAR alpha modulator (SPPARM alpha) that activates PPAR alpha 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 PPAR alpha agonists. Materials and Methods: To compare the effects of K-877 on PPAR alpha transcriptional activity with those of the classical PPAR alpha agonists Wy14643 (Wy) and fenofibrate (Feno), the cell-based PPAR alpha 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 PPAR alpha transcriptional activity more efficiently than the classical PPAR alpha 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 PPAR alpha. 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 PPAR alpha-modulating drug and can efficiently reduce plasma triglyceride levels, thereby alleviating the dysregulation of lipid metabolism.