Picrasidine N Is a Subtype-Selective PPARβ/δ Agonist

J Nat Prod. 2016 Apr 22;79(4):879-85. doi: 10.1021/acs.jnatprod.5b00909. Epub 2016 Mar 30.

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.

MeSH terms

  • Alkaloids / chemistry
  • Alkaloids / isolation & purification
  • Alkaloids / pharmacology*
  • Animals
  • Gene Expression Regulation
  • Molecular Structure
  • PPAR alpha / agonists
  • PPAR delta / agonists
  • PPAR gamma / agonists
  • PPAR-beta / agonists
  • Picrasma / chemistry*

Substances

  • Alkaloids
  • PPAR alpha
  • PPAR delta
  • PPAR gamma
  • PPAR-beta
  • picrasidine N