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

<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.