The Nuclear Receptor Peroxisome Proliferator-Activated Receptor-α Mediates the Anti-Inflammatory Actions of Palmitoylethanolamide
Open accessAbstract
Palmitoylethanolamide (PEA), the naturally occurring amide of palmitic acid and ethanolamine, reduces pain and inflammation through an as-yet-uncharacterized mechanism. Here, we identify the nuclear receptor peroxisome proliferator-activated receptor-alpha (PPAR-alpha) as the molecular target responsible for the anti-inflammatory properties of PEA. PEA selectively activates PPAR-alpha in vitro with an EC(50) value of 3.1 +/- 0.4 microM and induces the expression of PPAR-alpha mRNA when applied topically to mouse skin. In two animal models, carrageenan-induced paw edema and phorbol ester-induced ear edema, PEA attenuates inflammation in wild-type mice but has no effect in mice deficient in PPAR-alpha. The natural PPAR-alpha agonist oleoylethanolamide (OEA) and the synthetic PPAR-alpha agonists GW7647 and Wy-14643 mimic these effects in a PPAR-alpha-dependent manner. These findings indicate that PPAR-alpha mediates the anti-inflammatory effects of PEA and suggest that this fatty-acid ethanolamide may serve, like its analog OEA, as an endogenous ligand of PPAR-alpha.
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FAAH hydrolyzes PEA, which does not bind cannabinoid receptors but functions as an endogenous ligand for PPAR-α.
“Besides serving as the major catabolic enzyme of AEA, FAAH hydrolyzes other bioactive lipids, such as N-palmitoylethanolamine (PEA) (Fezza et al, 2008), which does not bind cannabinoid receptors, but functions as an endogenous ligand for peroxisome proliferator receptor-α (PPAR-α) (Lo Verme et al, 2005).”
From The endogenous cannabinoid system: a budding source of targets for treating inflammatory and neuropathic pain (2018) · cites this paper as Lo Verme et al, 2005
PEA does not bind cannabinoid receptors and has been described as an endogenous ligand for PPAR-α.
“PEA does not bind cannabinoid receptors and has recently been described as an endogenous ligand for peroxisome proliferator receptor-α (PPAR-α).26”
From Cannabinoids as Pharmacotherapies for Neuropathic Pain: From the Bench to the Bedside (2009) · cites this paper as [26]
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- Authors
- Lo Verme, J., Fu, J., Astarita, G., La Rana, G., Russo, R., Calignano, A., & Piomelli, D.
- Affiliations
- University of California, Irvine (US)
- Venue
- Molecular Pharmacology
- Publisher
- Elsevier BV
- Published
- 2005-01
- Volume
- 67
- Issue
- 1
- Pages
- 15-19
- ISSN
- 0026-895X (ISSN-L)
- OpenAlex
- W2165128851
- Cited by
- 882
- References
- 42
- Citations by year
- 2026: 27 · 2025: 28 · 2024: 45 · 2023: 34 · 2022: 57 · 2021: 57 · 2020: 54 · 2019: 38 · 2018: 44 · 2017: 46 · 2016: 42 · 2015: 51 · 2014: 52 · 2013: 35 · 2012: 55
- FWCI
- 10.66
- Type
- journal article
- Language
- en
- Open access
- green
- escholarship.org
- Locations
- Molecular Pharmacology (publishedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Health Sciences › Nursing › Nutrition and Dietetics › Fatty Acid Research and Health
- Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
- Keywords
- palmitoylethanolamide, PPARα, anti-inflammatory activity, fatty acid ethanolamides, oleoylethanolamide, carrageenan-induced paw edema, topical application, GW7647, Wy-14,643, nuclear receptor signaling
- MeSH terms
- Amides, Animals, Anti-Inflammatory Agents, Non-Steroidal, Base Sequence, Carrageenan, Crosses, Genetic, Edema, Ethanolamines, HeLa Cells, Humans, Male, Mice, Inbred C57BL, Palmitic Acids, Tetradecanoylphorbol Acetate, Polymerase Chain Reaction, DNA Primers, Mice, Knockout, PPAR alpha, Mice, Endocannabinoids
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