title: Transcriptome Analysis of K-877 (a Novel Selective PPARα Modulator (SPPARMα))-Regulated Genes in Primary Human Hepatocytes and the Mouse Liver.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Laboratory for Systems Biology and Medicine (LSBM), Research Center for Advanced Science and Technology (RCAST), University of Tokyo.
authors.forename: Sana
authors.initials: S
authors.lastname: Raza-Iqbal
authors.forename: Toshiya
authors.initials: T
authors.lastname: Tanaka
authors.forename: Motonobu
authors.initials: M
authors.lastname: Anai
authors.forename: Takeshi
authors.initials: T
authors.lastname: Inagaki
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Matsumura
authors.forename: Kaori
authors.initials: K
authors.lastname: Ikeda
authors.forename: Akashi
authors.initials: A
authors.lastname: Taguchi
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
authors.forename: Juro
authors.initials: J
authors.lastname: Sakai
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Kodama
mesh_terms: D000818:Animals; D001583:Benzoxazoles / Q000494:pharmacology*; D002087:Butyrates / Q000494:pharmacology*; D018929:Cell Culture Techniques; D016000:Cluster Analysis; D011345:Fenofibrate / Q000031:analogs & derivatives / Q000494:pharmacology; D020869:Gene Expression Profiling; D022781:Hepatocytes / Q000187:drug effects*; D006801:Humans; D000960:Hypolipidemic Agents / Q000494:pharmacology; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D051379:Mice; D046509:Tissue Culture Techniques; D059467:Transcriptome / Q000187:drug effects*
chemical_list: D001583:Benzoxazoles; D002087:Butyrates; D000960:Hypolipidemic Agents; C000603947:K-877 compound; C006012:fenofibric acid; D011345:Fenofibrate