Peroxisome Proliferator-Activated Receptor-Alpha Is Required for the Neurotrophic Effect of Oleic Acid in Neurons

J Neurochem. 2007 Nov;103(3):871-81. doi: 10.1111/j.1471-4159.2007.04807.x. Epub 2007 Aug 7.

Abstract

Oleic acid synthesized by astrocytes behaves as a neurotrophic factor for neurons, up-regulating the molecular markers of axonal and dendritic outgrowth, growth-associated protein 43 and microtubule-associated protein 2. In this work, the nature of the receptor involved in this neurotrophic effect was investigated. As oleic acid has been reported to be a ligand and activator of the peroxisome proliferator-activated receptor (PPAR), we focus on this family of receptors. Our results show that PPARalpha, beta/delta, and gamma are expressed in neurons in culture. However, only the agonists of PPARalpha, Wy14643, GW7647 and oleoylethanolamide, promoted neuronal differentiation, while PPAR beta/delta and gamma agonists did not modify neuronal differentiation. Consequently, we investigated the involvement of PPARalpha (Nr1c1) in oleic acid-induced neuronal differentiation. Our results indicate that oleic acid activates PPARalpha in neurons. In addition, the effect of oleic acid on neuronal morphology, growth-associated protein 43 and microtubule-associated protein 2 expression decreases in neurons after PPARalpha has been silenced by small interfering RNA. Taken together, our results suggest that PPARalpha could be the receptor for oleic acid in neurons, further broadening the range of functions attributed to this family of transcription factors. Although several works have reported that PPARalpha could be involved in neuroprotection, the present work provides the first evidence suggesting a role of PPARalpha in neuronal differentiation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Butyrates / pharmacology
  • Cell Differentiation / drug effects
  • Cell Differentiation / physiology*
  • Cell Shape / drug effects
  • Cell Shape / physiology
  • Cells, Cultured
  • Central Nervous System / cytology
  • Central Nervous System / embryology*
  • Central Nervous System / metabolism*
  • GAP-43 Protein / drug effects
  • GAP-43 Protein / metabolism
  • Growth Cones / drug effects
  • Growth Cones / metabolism
  • Microtubule-Associated Proteins / drug effects
  • Microtubule-Associated Proteins / metabolism
  • Nerve Growth Factors / metabolism*
  • Nerve Growth Factors / pharmacology
  • Neurites / drug effects
  • Neurites / metabolism
  • Neurons / cytology
  • Neurons / drug effects
  • Neurons / metabolism*
  • Oleic Acid / metabolism*
  • Oleic Acid / pharmacology
  • PPAR alpha / agonists
  • PPAR alpha / genetics
  • PPAR alpha / metabolism*
  • Phenylurea Compounds / pharmacology
  • Pyrimidines / pharmacology
  • RNA, Small Interfering / genetics
  • Rats
  • Rats, Wistar

Substances

  • Butyrates
  • GAP-43 Protein
  • GW 7647
  • Microtubule-Associated Proteins
  • Nerve Growth Factors
  • PPAR alpha
  • Phenylurea Compounds
  • Pyrimidines
  • RNA, Small Interfering
  • Oleic Acid
  • pirinixic acid