Search our Database of Scientific Publications and Authors

I’m looking for a
    Transcriptome Analysis of K-877 (a Novel Selective PPARα Modulator (SPPARMα))-Regulated Genes in Primary Human Hepatocytes and the Mouse Liver.
    J Atheroscler Thromb 2015 Aug 4;22(8):754-72. Epub 2015 Jun 4.
    Laboratory for Systems Biology and Medicine (LSBM), Research Center for Advanced Science and Technology (RCAST), University of Tokyo.
    Aim: 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.

    Methods: 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.

    Results: 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 Ppara-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 (VLDLR, FGF21, ABCA1, MBL2, ENPEP) in human hepatocytes.

    Conclusion: 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.

    Similar Publications

    Comparative analysis of gene regulation by the transcription factor PPARalpha between mouse and human.
    PLoS One 2009 Aug 27;4(8):e6796. Epub 2009 Aug 27.
    Nutrigenomics Consortium, Top Institute (TI) Food and Nutrition, Wageningen, The Netherlands.
    Background: Studies in mice have shown that PPARalpha is an important regulator of hepatic lipid metabolism and the acute phase response. However, little information is available on the role of PPARalpha in human liver. Here we set out to compare the function of PPARalpha in mouse and human hepatocytes via analysis of target gene regulation. Read More
    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 Jan 13. Epub 2017 Jan 13.
    Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.
    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. Read More
    High glucose potentiates L-FABP mediated fibrate induction of PPARα in mouse hepatocytes.
    Biochim Biophys Acta 2013 Aug 6;1831(8):1412-25. Epub 2013 Jun 6.
    Department of Physiology and Pharmacology, Texas A&M University, TVMC, College Station, TX 77843-4466, USA.
    Although liver fatty acid binding protein (L-FABP) binds fibrates and PPARα in vitro and enhances fibrate induction of PPARα in transformed cells, the functional significance of these findings is unclear, especially in normal hepatocytes. Studies with cultured primary mouse hepatocytes show that: 1) At physiological (6mM) glucose, fibrates (bezafibrate, fenofibrate) only weakly activated PPARα transcription of genes in LCFA β-oxidation; 2) High (11-20mM) glucose, but not maltose (osmotic control), significantly potentiated fibrate-induction of mRNA of these and other PPARα target genes to increase LCFA β-oxidation. These effects were associated with fibrate-mediated redistribution of L-FABP into nuclei-an effect prolonged by high glucose-but not with increased de novo fatty acid synthesis from glucose; 3) Potentiation of bezafibrate action by high glucose required an intact L-FABP/PPARα signaling pathway as shown with L-FABP null, PPARα null, PPARα inhibitor-treated WT, or PPARα-specific fenofibrate-treated WT hepatocytes. Read More