Functional and Structural Insights into Human PPARα/δ/γ Subtype Selectivity of Bezafibrate, Fenofibric Acid, and Pemafibrate
Open accessAbstract
Among the agonists against three peroxisome proliferator-activated receptor (PPAR) subtypes, those against PPARα (fibrates) and PPARγ (glitazones) are currently used to treat dyslipidemia and type 2 diabetes, respectively, whereas PPARδ agonists are expected to be the next-generation metabolic disease drug. In addition, some dual/pan PPAR agonists are currently being investigated via clinical trials as one of the first curative drugs against nonalcoholic fatty liver disease (NAFLD). Because PPARα/δ/γ share considerable amino acid identity and three-dimensional structures, especially in ligand-binding domains (LBDs), clinically approved fibrates, such as bezafibrate, fenofibric acid, and pemafibrate, could also act on PPARδ/γ when used as anti-NAFLD drugs. Therefore, this study examined their PPARα/δ/γ selectivity using three independent assays—a dual luciferase-based GAL4 transactivation assay for COS-7 cells, time-resolved fluorescence resonance energy transfer-based coactivator recruitment assay, and circular dichroism spectroscopy-based thermostability assay. Although the efficacy and efficiency highly varied between agonists, assay types, and PPAR subtypes, the three fibrates, except fenofibric acid that did not affect PPARδ-mediated transactivation and coactivator recruitment, activated all PPAR subtypes in those assays. Furthermore, we aimed to obtain cocrystal structures of PPARδ/γ-LBD and the three fibrates via X-ray diffraction and versatile crystallization methods, which we recently used to obtain 34 structures of PPARα-LBD cocrystallized with 17 ligands, including the fibrates. We herein reveal five novel high-resolution structures of PPARδ/γ–bezafibrate, PPARγ–fenofibric acid, and PPARδ/γ–pemafibrate, thereby providing the molecular basis for their application beyond dyslipidemia treatment.
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Fenofibrate is a selective PPAR-α agonist, whereas bezafibrate acts as a pan-PPAR agonist (α, δ, γ), which may account for broader biochemical and symptomatic benefits observed with bezafibrate.
“The difference may relate to pharmacologic profiles: fenofibrate is a selective PPAR-α agonist, whereas bezafibrate acts as a pan-PPAR agonist (α, δ, γ), which may account for broader biochemical and symptomatic benefits observed with bezafibrate [41].”
From Second-Line Therapies in Primary Biliary Cholangitis: A Comparative Review of Obeticholic Acid, Fibrates, Seladelpar, and Elafibranor (2025) · cites this paper as [41]
The Discussion (page unavailable) describes bezafibrate as a pan-PPAR agonist and says fenofibric acid, fenofibrate’s active metabolite, is recognized as PPARα-selective in clinical settings. It also finds that fenofibric acid activates PPARγ in vitro, calling it a PPARα/γ dual agonist. The Discussion suggests bezafibrate’s multiple PPAR actions may contribute to improved biochemical measures, but it does not establish broader symptomatic benefits or a clinical benefit comparison with fenofibrate. (LLM, conf=0.88)
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- Authors
- Honda, A., Kamata, S., Akahane, M., Machida, Y., Uchii, K., Shiiyama, Y., Habu, Y., Miyawaki, S., Kaneko, C., Oyama, T., & Ishii, I.
- Affiliations
- Showa Pharmaceutical University (JP)
- University of Yamanashi (JP)
- Corresponding author
- Ishii, Isao
- Venue
- International Journal of Molecular Sciences
- Publisher
- MDPI AG
- Published
- 2022-04-25
- Volume
- 23
- Issue
- 9
- Pages
- 4726
- ISSN
- 1422-0067 (ISSN-L)
- PMC
- PMC9102038
- OpenAlex
- W4224663364
- Cited by
- 32
- References
- 45
- Citations by year
- 2026: 7 · 2025: 10 · 2024: 5 · 2023: 6 · 2022: 4
- FWCI
- 2.04
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- International Journal of Molecular Sciences (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Japan Agency for Medical Research and Development (JP19am0101071)
- Ministry of Education, Culture, Sports, Science and Technology (19K16359)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Keywords
- PPARα, PPARδ, PPARγ, bezafibrate, fenofibric acid, pemafibrate, fibrates, ligand-binding domain, non-alcoholic fatty liver disease, dual PPAR agonists, coactivator recruitment, transcriptional activation, thermal stability
- MeSH terms
- Benzoxazoles, Bezafibrate, Butyrates, Diabetes Mellitus, Type 2, Humans, Ligands, Fenofibrate, PPAR alpha, PPAR delta, PPAR gamma, Dyslipidemias, Non-alcoholic Fatty Liver Disease
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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