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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.