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

Authors:
Toshiya Tanaka
Toshiya Tanaka
University of Tokyo
Japan
Motonobu Anai
Motonobu Anai
Graduate School of Medicine
Japan
Takeshi Inagaki
Takeshi Inagaki
Wakayama Medical University
Japan
Yoshihiro Matsumura
Yoshihiro Matsumura
Oregon Health and Science University
Kaori Ikeda
Kaori Ikeda
Tokyo University of Marine Science and Technology
Japan
Akashi Taguchi
Akashi Taguchi
University of Tokyo
Japan
Frank J Gonzalez
Frank J Gonzalez
Laboratory of Metabolism
Kalamazoo | United States

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.
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August 2015
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