title: Picrasidine N Is a Subtype-Selective PPARβ/δ Agonist.
abstract: Recently, growing evidence of the pivotal roles of peroxisome proliferator-activated receptor (PPAR) β/δ in various physiological functions, including lipid homeostasis, cancer, and inflammation, has raised interest in this receptor. In this study, the naturally occurring dimeric alkaloid picrasidine N (1) from Picrasma quassioides was identified as a novel PPARβ/δ agonist from a library consisting of plant extracts and natural compounds using a mammalian one-hybrid assay, and this compound was characterized. Compound 1 activated PPARβ/δ but did not activate or slightly activated PPARα and PPARγ. Furthermore, a peroxisome proliferator response element-driven luciferase reporter gene assay demonstrated that 1 enhanced PPARβ/δ transcriptional activity. Moreover, 1 selectively induced mRNA expression of ANGPTL4, which is a PPAR target gene. This observation is quite different from previously identified synthetic PPARβ/δ agonists, which can induce the expression of not only ANGPTL4 but also other PPAR target genes, such as ADRP, PDK4, and CPT-1. These results demonstrate that 1 is a potent subtype-selective and gene-selective PPARβ/δ agonist, suggesting its potential as a lead compound for further drug development. This compound would also be a useful chemical tool for elucidating the mechanism of PPARβ/δ-regulated specific gene expression and the biological significance of PPARβ/δ.
authors.affiliation: College of Life Science, Northeast Forestry University , Harbin 150040, People's Republic of China.
authors.forename: Shuai
authors.initials: S
authors.lastname: Zhao
authors.affiliation: Department of Molecular Toxicology, Faculty of Pharmaceutical Sciences, Toho University , Miyama 2-2-1, Funabashi, Chiba 274-8510, Japan.
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Kanno
authors.affiliation: Faculty of Pharmaceutical Sciences, Toho University , Miyama 2-2-1, Funabashi, Chiba 274-8510, Japan.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Molecular Toxicology, Faculty of Pharmaceutical Sciences, Toho University , Miyama 2-2-1, Funabashi, Chiba 274-8510, Japan.
authors.forename: Honami
authors.initials: H
authors.lastname: Wakatabi
authors.affiliation: Faculty of Pharmaceutical Sciences, Toho University , Miyama 2-2-1, Funabashi, Chiba 274-8510, Japan.
authors.forename: Tatsunori
authors.initials: T
authors.lastname: Sasaki
authors.affiliation: Faculty of Pharmaceutical Sciences, Toho University , Miyama 2-2-1, Funabashi, Chiba 274-8510, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Koike
authors.affiliation: Department of Molecular Toxicology, Faculty of Pharmaceutical Sciences, Toho University , Miyama 2-2-1, Funabashi, Chiba 274-8510, Japan.
authors.forename: Kiyomitsu
authors.initials: K
authors.lastname: Nemoto
authors.affiliation: College of Life Science, Northeast Forestry University , Harbin 150040, People's Republic of China.
authors.forename: Huicheng
authors.initials: H
authors.lastname: Li
mesh_terms: D000470:Alkaloids / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D000818:Animals; D005786:Gene Expression Regulation; D015394:Molecular Structure; D047493:PPAR alpha / Q000819:agonists; D047494:PPAR delta / Q000819:agonists; D047495:PPAR gamma / Q000819:agonists; D048068:PPAR-beta / Q000819:agonists; D032270:Picrasma / Q000737:chemistry*
chemical_list: D000470:Alkaloids; D047493:PPAR alpha; D047494:PPAR delta; D047495:PPAR gamma; D048068:PPAR-beta; C000610376:picrasidine N