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Article

Peroxisome Proliferator-Activated Receptor α/δ/γ Activation Profile by Endogenous Long-Chain Fatty Acids

by
Akihiro Honda
†,
Aoi Hosoda
†,
Waka Kamichatani
,
Midori Ogasawara
,
Shiori Miyazaki
,
Nonoka Kashiwagi
,
Shotaro Kamata
and
Isao Ishii
*
Department of Health Chemistry, Showa Pharmaceutical University, Machida, Tokyo 194-8543, Japan
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Int. J. Mol. Sci. 2025, 26(24), 12020; https://doi.org/10.3390/ijms262412020 (registering DOI)
Submission received: 12 November 2025 / Revised: 10 December 2025 / Accepted: 11 December 2025 / Published: 13 December 2025
(This article belongs to the Special Issue PPAR Update: Molecular Mechanisms and Therapeutic Perspectives)
Review Reports Versions Notes

Abstract

There is a wealth of information available about endogenous fatty acid ligands for peroxisome proliferator-activated receptor α/δ/γ (PPARα/δ/γ); however, there are few comparative studies of PPARα/δ/γ activation using standardized experimental systems. This study investigated which of 14 major free long-chain fatty acids (LCFAs: C12:0–C22:6) and 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) activate PPARα/δ/γ using a coactivator recruitment assay. We recently discovered that eight different synthetic PPAR agonists recruit four different coactivator peptides (PGC1α, CBP, SRC1, TRAP220) with varying potency and efficacy, so we examined the ligand-concentration-dependent recruitment of these four coactivators. All 15 fatty acids (FAs) activated PPARα/δ at high concentrations, but only palmitic acid, stearic acid, oleic acid, and linoleic acid significantly activated PPARα/δ at physiologically relevant concentrations. Lauric acid, myristic acid, palmitic acid, and 15d-PGJ2 activated PPARγ at high concentrations, but only palmitic acid slightly activated PPARγ at physiologically relevant concentrations. FA ligands exhibited different coactivator preference compared to synthetic PPAR agonists, including approved drugs such as pemafibrate, seladelpar, and pioglitazone, suggesting that these agonists may regulate target gene transcription in a different manner than natural FA ligands. Such differences may be relevant to the pathogenesis of side effects of synthetic PPAR agonists occasionally observed in (pre)clinical studies.
Keywords: coactivator recruitment; 15-deoxy-Δ12,14-prostaglandin J2; endogenous ligand; ligand-binding domain; non-esterified fatty acids; nuclear receptor; peroxisome proliferator-activated receptor; therapeutics; time-resolved fluorescence resonance energy transfer; transcriptional factor coactivator recruitment; 15-deoxy-Δ12,14-prostaglandin J2; endogenous ligand; ligand-binding domain; non-esterified fatty acids; nuclear receptor; peroxisome proliferator-activated receptor; therapeutics; time-resolved fluorescence resonance energy transfer; transcriptional factor

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MDPI and ACS Style

Honda, A.; Hosoda, A.; Kamichatani, W.; Ogasawara, M.; Miyazaki, S.; Kashiwagi, N.; Kamata, S.; Ishii, I. Peroxisome Proliferator-Activated Receptor α/δ/γ Activation Profile by Endogenous Long-Chain Fatty Acids. Int. J. Mol. Sci. 2025, 26, 12020. https://doi.org/10.3390/ijms262412020

AMA Style

Honda A, Hosoda A, Kamichatani W, Ogasawara M, Miyazaki S, Kashiwagi N, Kamata S, Ishii I. Peroxisome Proliferator-Activated Receptor α/δ/γ Activation Profile by Endogenous Long-Chain Fatty Acids. International Journal of Molecular Sciences. 2025; 26(24):12020. https://doi.org/10.3390/ijms262412020

Chicago/Turabian Style

Honda, Akihiro, Aoi Hosoda, Waka Kamichatani, Midori Ogasawara, Shiori Miyazaki, Nonoka Kashiwagi, Shotaro Kamata, and Isao Ishii. 2025. "Peroxisome Proliferator-Activated Receptor α/δ/γ Activation Profile by Endogenous Long-Chain Fatty Acids" International Journal of Molecular Sciences 26, no. 24: 12020. https://doi.org/10.3390/ijms262412020

APA Style

Honda, A., Hosoda, A., Kamichatani, W., Ogasawara, M., Miyazaki, S., Kashiwagi, N., Kamata, S., & Ishii, I. (2025). Peroxisome Proliferator-Activated Receptor α/δ/γ Activation Profile by Endogenous Long-Chain Fatty Acids. International Journal of Molecular Sciences, 26(24), 12020. https://doi.org/10.3390/ijms262412020

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