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Identification of Picrasidine C as a Subtype-Selective PPARα Agonist
- Zhao, Shuai, Kanno, Yuichiro, Li, Wei, Sasaki, Tatsunori, Zhang, Xiangyu, Wang, Jian, Cheng, Maosheng, Koike, Kazuo, Nemoto, Kiyomitsu, Li, Huicheng
- Journal of natural products 2016 v.79 no.12 pp. 3127-3133
- Picrasma quassioides, agonists, alkaloids, antagonists, atherosclerosis, cholesterol metabolism, genes, glucose, hypercholesterolemia, lipids, luciferase, mammals, peroxisome proliferator-activated receptors, transcription (genetics)
- 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.