title: Identification and characterization of PPARα ligands in the hippocampus.
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.
authors.affiliation: Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois, USA.
authors.forename: Avik
authors.initials: A
authors.lastname: Roy
authors.affiliation: Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois, USA.
authors.forename: Madhuchhanda
authors.initials: M
authors.lastname: Kundu
authors.affiliation: Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois, USA.
authors.forename: Malabendu
authors.initials: M
authors.lastname: Jana
authors.affiliation: Medicinal and Synthetic Chemistry Core, Center for Molecular Innovation and Drug Discovery, Northwestern University, Evanston, Illinois, USA.
authors.forename: Rama K
authors.initials: RK
authors.lastname: Mishra
authors.affiliation: Research Resources Center, University of Illinois at Chicago, Chicago, Illinois, USA.
authors.forename: Yeni
authors.initials: Y
authors.lastname: Yung
authors.affiliation: High Throughput Analysis Laboratory and Department of Molecular Biosciences, Northwestern University, Evanston, Illinois, USA.
authors.forename: Chi-Hao
authors.initials: CH
authors.lastname: Luan
authors.affiliation: Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Frank J
authors.identifier: http://orcid.org/0000-0002-7990-2140
authors.initials: FJ
authors.lastname: Gonzalez
authors.affiliation: Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois, USA.|Division of Research and Development, Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois, USA.
authors.forename: Kalipada
authors.initials: K
authors.lastname: Pahan
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D006624:Hippocampus / Q000378:metabolism*; D006885:Hydroxybutyrates / Q000737:chemistry / Q000494:pharmacology*; D008024:Ligands; D051379:Mice; D018345:Mice, Knockout; D008958:Models, Molecular; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009829:Oleic Acids / Q000737:chemistry / Q000494:pharmacology; D047493:PPAR alpha / Q000378:metabolism*; D010169:Palmitic Acids / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: C000618321:3-hydroxy-2,2-dimethylbutyrate; D006885:Hydroxybutyrates; D008024:Ligands; D009829:Oleic Acids; D047493:PPAR alpha; D010169:Palmitic Acids; C029407:oleylamide; C014025:hexadecanamide