Identification of Isosilybin A from Milk Thistle Seeds as an Agonist of Peroxisome Proliferator-Activated Receptor Gamma

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• 作者：Eva-Maria Pferschy-Wenzig ; Atanas G. Atanasov ; Clemens Malainer ; Stefan M. Noha ; Olaf Kunert ; Daniela Schuster ; Elke H. Heiss ; Nicholas H. Oberlies ; Hildebert Wagner ; Rudolf Bauer ; Verena M. Dirsch
• 刊名：Journal of Natural Products
• 出版年：2014
• 出版时间：April 25, 2014
• 年：2014
• 卷：77
• 期：4
• 页码：842-847
• 全文大小：332K
• 年卷期：v.77,no.4(April 25, 2014)
• ISSN：1520-6025

文摘

Peroxisome proliferator-activated receptor gamma (PPAR纬) is a key regulator of glucose and lipid metabolism. Agonists of this nuclear receptor are used in the treatment of type 2 diabetes and are also studied as a potential treatment of other metabolic diseases, including nonalcoholic fatty liver disease. Silymarin, a concentrated phenolic mixture from milk thistle (Silybum marianum) seeds, is used widely as a supportive agent in the treatment of a variety of liver diseases. In this study, the PPAR纬 activation potential of silymarin and its main constituents was investigated. Isosilybin A (3) caused transactivation of a PPAR纬-dependent luciferase reporter in a concentration-dependent manner. This effect could be reversed upon co-treatment with the PPAR纬 antagonist T0070907. In silico docking studies suggested a binding mode for 3 distinct from that of the inactive silymarin constituents, with one additional hydrogen bond to Ser342 in the entrance region of the ligand-binding domain of the receptor. Hence, isosilybin A (3) has been identified as the first flavonolignan PPAR纬 agonist, suggesting its further investigation as a modulator of this nuclear receptor.