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

J Diabetes Investig. 2017 Jul;8(4):446-452. doi: 10.1111/jdi.12621. Epub 2017 Apr 25.


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.

Keywords: Lipid metabolism; Peroxisome proliferator-activated receptor-α; Selective peroxisome proliferator-activated receptor-α modulator.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Benzoxazoles / pharmacology*
  • Butyrates / pharmacology*
  • Cell Line
  • Drug Evaluation, Preclinical
  • Fenofibrate / pharmacology
  • Gene Expression / drug effects*
  • Hypolipidemic Agents / pharmacology
  • Lipid Metabolism / drug effects*
  • Liver / drug effects*
  • Liver / metabolism
  • Male
  • Mice, Inbred C57BL
  • PPAR alpha / agonists*
  • Pyrimidines / pharmacology
  • X-Box Binding Protein 1 / metabolism


  • Benzoxazoles
  • Butyrates
  • Hypolipidemic Agents
  • K-877 compound
  • PPAR alpha
  • Pyrimidines
  • X-Box Binding Protein 1
  • Xbp1 protein, mouse
  • pirinixic acid
  • Fenofibrate