Identification of Picrasidine C as a Subtype-Selective PPARα Agonist

J Nat Prod. 2016 Dec 23;79(12):3127-3133. doi: 10.1021/acs.jnatprod.6b00883. Epub 2016 Dec 13.

Abstract

Picrasidine C (1), a dimeric β-carboline-type alkaloid isolated from the root of Picrasma quassioides, was identified to have PPARα agonistic activity by a mammalian one-hybrid assay from a compound library. Among the PPAR subtypes, 1 selectively activated PPARα in a concentration-dependent manner. Remarkably, 1 also promoted PPARα transcriptional activity by a peroxisome proliferator response element-driven luciferase reporter assay. Furthermore, 1 induced the expression of PPARα-regulated genes involved in lipid, glucose, and cholesterol metabolism, such as CPT-1, PPARα, PDK4, and ABCA1, which was abrogated by the PPARα antagonist MK-886, indicating that the effect of 1 was dependent on PPARα activation. This is the first report to demonstrate 1 to be a subtype-selective PPARα agonist with potential application in treating metabolic diseases, such as hyperlipidemia, atherosclerosis, and hypercholesterolemia.

MeSH terms

  • Alkaloids / chemistry
  • Alkaloids / isolation & purification*
  • Alkaloids / pharmacology*
  • Animals
  • Atherosclerosis / drug therapy
  • Carbolines / chemistry
  • Carbolines / isolation & purification*
  • Carbolines / pharmacology*
  • Cholesterol / metabolism
  • Glucose / metabolism
  • Hypercholesterolemia / drug therapy
  • Indoles / pharmacology
  • Lipid Metabolism
  • Lipids
  • Mice
  • Molecular Structure
  • PPAR alpha / agonists*
  • PPAR alpha / genetics
  • Picrasma / chemistry*
  • Transcription Factors / metabolism

Substances

  • Alkaloids
  • Carbolines
  • Indoles
  • Lipids
  • PPAR alpha
  • Transcription Factors
  • MK-886
  • norharman
  • Cholesterol
  • Glucose