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  3. Identification and characterization of PPARα ligands in the hippocampus

Identification and characterization of PPARα ligands in the hippocampus

  • Nat Chem Biol. 2016 Dec;12(12):1075-1083. doi: 10.1038/nchembio.2204.
Avik Roy 1,  Madhuchhanda Kundu 1,  Malabendu Jana 1,  Rama K Mishra 2,  Yeni Yung 3,  Chi-Hao Luan 4,  Frank J Gonzalez 5,  Kalipada Pahan 1 6
Affiliations

Affiliations

  • 1 Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois, USA.
  • 2 Medicinal and Synthetic Chemistry Core, Center for Molecular Innovation and Drug Discovery, Northwestern University, Evanston, Illinois, USA.
  • 3 Research Resources Center, University of Illinois at Chicago, Chicago, Illinois, USA.
  • 4 High Throughput Analysis Laboratory and Department of Molecular Biosciences, Northwestern University, Evanston, Illinois, USA.
  • 5 Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
  • 6 Division of Research and Development, Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois, USA.
PMID: 27748752 DOI: 10.1038/nchembio.2204
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.

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