Identification and characterization of PPARα ligands in the hippocampus

Avik Roy, Madhuchhanda Kundu, Malabendu Jana, Rama K. Mishra, Yeni Yung, Chi Hao Luan, Frank J. Gonzalez, Kalipada Pahan*

*Corresponding author for this work

Research output: Contribution to journalArticle

25 Scopus citations

Abstract

Peroxisome proliferator-activated receptor-α (PPARα) regulates hepatic fatty acid catabolism and mediates the metabolic response to starvation. Recently we found that PPARα is constitutively activated in nuclei of hippocampal neurons and controls plasticity via direct transcriptional activation of CREB. Here we report the discovery of three endogenous PPARα ligands - 3-hydroxy-(2,2)-dimethyl butyrate, hexadecanamide, and 9-octadecenamide - in mouse brain hippocampus. Mass spectrometric detection of these compounds in mouse hippocampal nuclear extracts, in silico interaction studies, time-resolved FRET analyses, and thermal shift assay results clearly indicated that these three compounds served as ligands of PPARα. Site-directed mutagenesis studies further revealed that PPARα Y464 and Y314 are involved in binding these hippocampal ligands. Moreover, these ligands activated PPARα and upregulated the synaptic function of hippocampal neurons. These results highlight the discovery of hippocampal ligands of PPARα capable of modulating synaptic functions.

Original languageEnglish (US)
Pages (from-to)1075-1083
Number of pages9
JournalNature Chemical Biology
Volume12
Issue number12
DOIs
StatePublished - Dec 1 2016

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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