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

Kenta Takei, Yoshimi Nakagawa*, Yunong Wang, Song iee Han, Aoi Satoh, Motohiro Sekiya, Takashi Matsuzaka, Hitoshi Shimano

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

40 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)214-222
Number of pages9
JournalJournal of Pharmacological Sciences
Volume133
Issue number4
DOIs
StatePublished - 2017/04/01

Keywords

  • Cholesterol absorption
  • HDL cholesterol
  • PPARα
  • SPPARMα

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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