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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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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Transcriptome analysis showed that induced and suppressed gene groups clearly differed between pemafibrate and fenofibrate in primary human hepatocytes and mouse liver.
“Transcriptome analysis of pemafibrate-regulated genes in primary human hepatocytes and the mouse liver has indicated that the induced and suppressed gene groups clearly differed between pemafibrate and fenofibrate [51].”
From Pemafibrate, a new selective PPARα modulator: drug concept and its clinical applications for dyslipidemia and metabolic diseases (2020) · cites this paper as [51]
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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)
- ORCID
- Venue
- Journal of Atherosclerosis and Thrombosis
- Publisher
- Japan Atherosclerosis Society
- Published
- 2015
- Volume
- 22
- Issue
- 8
- Pages
- 754-772
- ISSN
- 1340-3478 (ISSN-L)
- 1880-3873
- PMC
- PMC7783548
- 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
- hybrid
- doi.org
- 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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