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Open Access Publications from the University of California

The nuclear receptor peroxisome proliferator-activated receptor-α mediates the anti-inflammatory actions of palmitoylethanolamide

  • Author(s): Lo Verme, J
  • Fu, J
  • Astarita, G
  • La Rana, G
  • Russo, R
  • Calignano, A
  • Piomelli, D
  • et al.

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-α (PPAR-α) as the molecular target responsible for the anti-inflammatory properties of PEA. PEA selectively activates PPAR-α in vitro with an EC50value of 3.1 ± 0.4 μM and induces the expression of PPAR-α 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-α. The natural PPAR-α agonist oleoylethanolamide (OEA) and the synthetic PPAR-α agonists GW7647 and Wy-14643 mimic these effects in a PPAR-α-dependent manner. These findings indicate that PPAR-α mediates the antiinflammatory effects of PEA and suggest that this fatty-acid ethanolamide may serve, like its analog OEA, as an endogenous ligand of PPAR-α.

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