Transcriptome Analysis of K-877 (a Novel Selective PPARα Modulator (SPPARMα))-Regulated Genes in Primary Human Hepatocytes and the Mouse Liver

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Author(s)

    • Raza-Iqbal Sana
    • Laboratory for Systems Biology and Medicine (LSBM), Research Center for Advanced Science and Technology (RCAST), University of Tokyo
    • Kodama Tatsuhiko
    • Laboratory for Systems Biology and Medicine (LSBM), Research Center for Advanced Science and Technology (RCAST), University of Tokyo
    • Tanaka Toshiya
    • Laboratory for Systems Biology and Medicine (LSBM), Research Center for Advanced Science and Technology (RCAST), University of Tokyo|Translational Systems Biology and Medicine Initiative Center for Disease Biology and Integrative Medicine, Faculty of Medicine, University Tokyo
    • Anai Motonobu
    • Laboratory for Systems Biology and Medicine (LSBM), Research Center for Advanced Science and Technology (RCAST), University of Tokyo
    • Inagaki Takeshi
    • Translational Systems Biology and Medicine Initiative Center for Disease Biology and Integrative Medicine, Faculty of Medicine, University Tokyo|Division of Metabolic Medicine, Research Center for Advanced Science and Technology (RCAST), University of Tokyo
    • Matsumura Yoshihiro
    • Division of Metabolic Medicine, Research Center for Advanced Science and Technology (RCAST), University of Tokyo
    • Ikeda Kaori
    • Translational Systems Biology and Medicine Initiative Center for Disease Biology and Integrative Medicine, Faculty of Medicine, University Tokyo
    • Taguchi Akashi
    • Laboratory for Systems Biology and Medicine (LSBM), Research Center for Advanced Science and Technology (RCAST), University of Tokyo
    • Gonzalez Frank J.
    • Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health
    • Sakai Juro
    • Translational Systems Biology and Medicine Initiative Center for Disease Biology and Integrative Medicine, Faculty of Medicine, University Tokyo|Division of Metabolic Medicine, Research Center for Advanced Science and Technology (RCAST), University of Tokyo

Abstract

<b><i>Aim</i></b><b>: </b>Selective PPARα modulators (SPPARMα) are under development for use as next-generation lipid lowering drugs. In the current study, to predict the pharmacological and toxicological effects of a novel SPPARMα K-877, comprehensive transcriptome analyses of K-877-treated primary human hepatocytes and mouse liver tissue were carried out.<br><b><i>Methods</i></b><b>: </b>Total RNA was extracted from the K-877 treated primary human hepatocytes and mouse liver and adopted to the transcriptome analysis. Using a cluster analysis, commonly and species specifically regulated genes were identified. Also, the profile of genes regulated by K-877 and fenofibrate were compared to examine the influence of different SPPARMα on the liver gene expression.<br><b><i>Results</i></b><b>: </b>Consequently, a cell-based transactivation assay showed that K-877 activates PPARα with much greater potency and selectivity than fenofibric acid, the active metabolite of clinically used fenofibrate. K-877 upregulates the expression of several fatty acid β-oxidative genes in human hepatocytes and the mouse liver. Almost all genes up- or downregulated by K-877 treatment in the mouse liver were also regulated by fenofibrate treatment. In contrast, the K-877-regulated genes in the mouse liver were not affected by K-877 treatment in the <i>Ppara</i>-null mouse liver. Depending on the species, the peroxisomal biogenesis-related gene expression was robustly induced in the K-877-treated mouse liver, but not human hepatocytes, thus suggesting that the clinical dose of K-877 may not induce peroxisome proliferation or liver toxicity in humans. Notably, K-877 significantly induces the expression of clinically beneficial target genes (<i>VLDLR</i>, <i>FGF21</i>, <i>ABCA1</i>, <i>MBL2</i>, <i>ENPEP</i>) in human hepatocytes.<br><b><i>Conclusion</i></b><b>: </b>These results indicate that changes in the gene expression induced by K-877 treatment are mainly mediated through PPARα activation. K-877 regulates the hepatic gene expression as a SPPARMα and thus may improve dyslipidemia as well as metabolic disorders, such as metabolic syndrome and type 2 diabetes, without untoward side effects.

Journal

  • Journal of Atherosclerosis and Thrombosis

    Journal of Atherosclerosis and Thrombosis 22(8), 754-772, 2015

    Japan Atherosclerosis Society

Codes

  • NII Article ID (NAID)
    130005095007
  • Text Lang
    ENG
  • ISSN
    1340-3478
  • Data Source
    J-STAGE 
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