Effects of K-877, a novel selective PPARα modulator, on small intestine contribute to the amelioration of hyperlipidemia in low-density lipoprotein receptor knockout mice

J Pharmacol Sci. 2017 Apr;133(4):214-222. doi: 10.1016/j.jphs.2017.02.003. Epub 2017 Feb 11.


Peroxisome proliferator-activated receptor α (PPARα) is a well-known therapeutic target for treating hyperlipidemia. K-877 is a novel selective PPARα modulator (SPPARMα) that enhances PPARα transcriptional activity with high selectivity and potency, resulting in reduced plasma lipid levels. This study aimed to evaluate the effects of K-877 on hyperlipidemia in low-density lipoprotein receptor knockout (Ldlr-/-) mice, a mouse model of atherosclerosis. We revealed that K-877 administration significantly decreased plasma triglyceride (TG) and total cholesterol (TC) levels and increased plasma high-density lipoprotein cholesterol (HDL-C) levels in Ldlr-/- mice. K-877 administration to Ldlr-/- mice efficiently increased the gene expression of PPARα and its target genes related to fatty acid oxidation in the liver and small intestine. The same treatment significantly increased ATP-binding cassette a1 gene expression in the liver and small intestine and reduced Niemann Pick C1-like 1 gene expression in the small intestine, suggesting that K-877 administration induced HDL-C production in the liver and small intestine and reduced cholesterol absorption in the small intestine. In conclusion, K-877 administration had pronounced effects on the liver and small intestine in Ldlr-/- mice. K-877 is an attractive PPARα-modulating drug for treating hyperlipidemia that works equally well in both the liver and small intestine.

Keywords: Cholesterol absorption; HDL cholesterol; PPARα; SPPARMα.

MeSH terms

  • Animals
  • Atherosclerosis / drug therapy*
  • Atherosclerosis / genetics*
  • Atherosclerosis / metabolism
  • Benzoxazoles / pharmacology*
  • Benzoxazoles / therapeutic use*
  • Butyrates / pharmacology*
  • Butyrates / therapeutic use*
  • Cholesterol / metabolism
  • Disease Models, Animal
  • Fatty Acids / metabolism
  • Gene Expression / drug effects*
  • Gene Knockout Techniques
  • Hyperlipidemias / drug therapy*
  • Hyperlipidemias / genetics*
  • Hyperlipidemias / metabolism
  • Intestinal Absorption / drug effects
  • Intestine, Small / metabolism*
  • Lipid Metabolism / drug effects*
  • Liver / metabolism
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Molecular Targeted Therapy
  • Oxidation-Reduction / drug effects
  • PPAR alpha / agonists*
  • PPAR alpha / genetics*
  • Receptors, LDL / genetics*


  • Benzoxazoles
  • Butyrates
  • Fatty Acids
  • K-877 compound
  • PPAR alpha
  • Receptors, LDL
  • Cholesterol