論文

2017年7月

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

Journal of diabetes investigation
  • Kenta Takei
  • ,
  • Song-Iee Han
  • ,
  • Yuki Murayama
  • ,
  • Aoi Satoh
  • ,
  • Fusaka Oikawa
  • ,
  • Hiroshi Ohno
  • ,
  • Yoshinori Osaki
  • ,
  • Takashi Matsuzaka
  • ,
  • Motohiro Sekiya
  • ,
  • Hitoshi Iwasaki
  • ,
  • Shigeru Yatoh
  • ,
  • Naoya Yahagi
  • ,
  • Hiroaki Suzuki
  • ,
  • Nobuhiro Yamada
  • ,
  • Yoshimi Nakagawa
  • ,
  • Hitoshi Shimano

8
4
開始ページ
446
終了ページ
452
記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.1111/jdi.12621

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.

リンク情報
DOI
https://doi.org/10.1111/jdi.12621
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/28084058
PubMed Central
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5497046
ID情報
  • DOI : 10.1111/jdi.12621
  • PubMed ID : 28084058
  • PubMed Central 記事ID : PMC5497046

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