Picrasidine N Is a Subtype-Selective PPARβ/δ Agonist

• Published in: Journal of natural products (Washington, D.C.) Vol. 79; no. 4; pp. 879 - 885
• Main Authors: Zhao, Shuai, Kanno, Yuichiro, Li, Wei, Wakatabi, Honami, Sasaki, Tatsunori, Koike, Kazuo, Nemoto, Kiyomitsu, Li, Huicheng
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society and American Society of Pharmacognosy 22.04.2016
• Subjects: agonists; alkaloids; Alkaloids - chemistry; Alkaloids - isolation & purification; Alkaloids - pharmacology; Animals; drugs; gene expression; Gene Expression Regulation; homeostasis; inflammation; lipids; luciferase; mammals; messenger RNA; Molecular Structure; neoplasms; peroxisome proliferator-activated receptors; Picrasma - chemistry; Picrasma quassioides; PPAR alpha - agonists; PPAR delta - agonists; PPAR gamma - agonists; PPAR-beta - agonists; reporter genes; transcription (genetics)
• ISSN: 0163-3864; 1520-6025; 1520-6025
• DOI: 10.1021/acs.jnatprod.5b00909

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.