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.
Original language | English |
---|---|
Pages (from-to) | 446-452 |
Number of pages | 7 |
Journal | Journal of Diabetes Investigation |
Volume | 8 |
Issue number | 4 |
DOIs | |
State | Published - 2017/07 |
Keywords
- Lipid metabolism
- Peroxisome proliferator-activated receptor-α
- Selective peroxisome proliferator-activated receptor-α modulator
ASJC Scopus subject areas
- Internal Medicine
- Endocrinology, Diabetes and Metabolism