title: Identification of isosilybin a from milk thistle seeds as an agonist of peroxisome proliferator-activated receptor gamma.
abstract: Peroxisome proliferator-activated receptor gamma (PPARγ) 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 PPARγ activation potential of silymarin and its main constituents was investigated. Isosilybin A (3) caused transactivation of a PPARγ-dependent luciferase reporter in a concentration-dependent manner. This effect could be reversed upon co-treatment with the PPARγ 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 PPARγ agonist, suggesting its further investigation as a modulator of this nuclear receptor.
authors.affiliation: Institute of Pharmaceutical Sciences, Department of Pharmacognosy, University Graz , Austria.
authors.forename: Eva-Maria
authors.initials: EM
authors.lastname: Pferschy-Wenzig
authors.forename: Atanas G
authors.initials: AG
authors.lastname: Atanasov
authors.forename: Clemens
authors.initials: C
authors.lastname: Malainer
authors.forename: Stefan M
authors.initials: SM
authors.lastname: Noha
authors.forename: Olaf
authors.initials: O
authors.lastname: Kunert
authors.forename: Daniela
authors.initials: D
authors.lastname: Schuster
authors.forename: Elke H
authors.initials: EH
authors.lastname: Heiss
authors.forename: Nicholas H
authors.initials: NH
authors.lastname: Oberlies
authors.forename: Hildebert
authors.initials: H
authors.lastname: Wagner
authors.forename: Rudolf
authors.initials: R
authors.lastname: Bauer
authors.forename: Verena M
authors.initials: VM
authors.lastname: Dirsch
mesh_terms: D017667:Adipocytes / Q000378:metabolism; D001549:Benzamides / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D008107:Liver Diseases / Q000188:drug therapy*; D020944:Silybum marianum / Q000737:chemistry*; D015394:Molecular Structure; D047495:PPAR gamma / Q000819:agonists*; D011725:Pyridines / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D012639:Seeds / Q000737:chemistry; D012838:Silymarin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D013237:Stereoisomerism
chemical_list: D001549:Benzamides; D047495:PPAR gamma; D011725:Pyridines; D018160:Receptors, Cytoplasmic and Nuclear; D012838:Silymarin; C458508:T 0070907; C523198:isosilybin A