Cited by 101Peroxisome Proliferator-Activated ReceptorsDrug-Induced Hepatotoxicity and ProtectionPharmacogenetics and Drug Metabolism

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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Raza-Iqbal, Sana, Tanaka, Toshiya, Anai, Motonobu, Inagaki, Takeshi, Matsumura, Yoshihiro, Ikeda, Kaori, Taguchi, Akashi, Gonzalez, Frank J. +2 more·2015·Journal of Atherosclerosis and Thrombosis

Abstract

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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  1. [60]Kim H, Mendez R, Zheng Z, Chang L, Cai J, Zhang R, Zhang K: Liver-enriched transcription factor CREBH interacts with peroxisome proliferator-activated receptor α to regulate metabolic hormone FGF21. Endocrinology, 2014; 155: 769– 782 24424044 PMC3929740

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Authors
Raza-Iqbal, S., Tanaka, T., Anai, M., Inagaki, T., Matsumura, Y., Ikeda, K., Taguchi, A., Gonzalez, F. J., Sakai, J., & Kodama, T.
Affiliations
  • Research Center for Advanced Science and Technology, The University of Tokyo (JP)
  • Center for Disease Biology and Integrative Medicine, The University of Tokyo (JP)
  • National Institutes of Health (US)
Venue
Journal of Atherosclerosis and Thrombosis
Published
2015
Volume
22
Issue
8
Pages
754-772
ISSN
  • 1340-3478 (ISSN-L)
  • 1880-3873
OpenAlex
W1615613652
Cited by
100
References
59
Citations by year
2026: 2 · 2025: 5 · 2024: 12 · 2023: 6 · 2022: 10 · 2021: 10 · 2020: 13 · 2019: 15 · 2018: 12 · 2017: 10 · 2016: 3 · 2015: 2
FWCI
3.91
Type
journal article
Language
en
Open access
Licence
cc-by-nc-sa
Locations
  • Journal of Atherosclerosis and Thrombosis (publishedVersion, cc-by-nc-sa)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Ministry of Education, Culture, Sports, Science and Technology
  • National Institutes of Health
  • Japan Society for the Promotion of Science (22229009, 26560395)
  • National Cancer Institute (Z01BC005561)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
Keywords
PPARα activation, hepatic gene expression, human hepatocytes, mouse liver, fenofibrate, fatty acid beta-oxidation, peroxisome proliferation, dyslipidemia, lipid-lowering drugs, VLDLR, FGF21, ABCA1, MBL2, glutamyl aminopeptidase, type 2 diabetes, metabolic syndrome
MeSH terms
Animals, Hypolipidemic Agents, Benzoxazoles, Butyrates, Humans, Liver, Fenofibrate, Cluster Analysis, Cell Culture Techniques, Gene Expression Profiling, Hepatocytes, Tissue Culture Techniques, Mice, Transcriptome

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