title: A novel LXR-alpha activator identified from the natural product Gynostemma pentaphyllum.
abstract: Liver X receptors (LXR) play an important role in cholesterol homeostasis by serving as regulatory sensors of cholesterol levels in tissues. The present study reports a novel LXR-alpha activator, (20S)-2alpha, 3beta, 12beta, 24(S)-pentahydroxydammar-25-ene 20-O-beta-d-glucopyranoside (TR1), a dammarane-type gynosaponin, isolated from the herbal medicine, Gynostemma pentaphyllum. Gynosaponin TR1 demonstrated greater selectivity toward activation of the LXR-alpha isoform than LXR-beta in HEK293 cells. TR1 selectively enhanced LXR-mediated transcriptional activation and protein expression of ABCA1 and apoE gene expression and secretion in THP-1-derived macrophages. The selectivity of TR1 for LXR-alpha was consistent with ligand docking studies, which showed favourable interaction of TR1 in the LXR-alpha-binding domain, whereas the presence of the sugar substituent interfered with binding to the LXR-beta site. Findings from the present study may provide insight into the development of pharmaceutical agents for treating atherosclerosis.
authors.affiliation: Pharmaceutical Chemistry, Herbal Medicines Research and Education Centre, Faculty of Pharmacy, A15, S322, University of Sydney, NSW 2006, Australia.
authors.forename: Tom Hsun-Wei
authors.initials: TH
authors.lastname: Huang
authors.forename: Valentina
authors.initials: V
authors.lastname: Razmovski-Naumovski
authors.forename: Noeris K
authors.initials: NK
authors.lastname: Salam
authors.forename: Rujee K
authors.initials: RK
authors.lastname: Duke
authors.forename: Van Hoan
authors.initials: VH
authors.lastname: Tran
authors.forename: Colin C
authors.initials: CC
authors.lastname: Duke
authors.forename: Basil D
authors.initials: BD
authors.lastname: Roufogalis
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D001057:Apolipoproteins E / Q000235:genetics; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000187:drug effects* / Q000235:genetics; D029774:Gynostemma / Q000737:chemistry*; D006801:Humans; D008024:Ligands; D000071518:Liver X Receptors; D008958:Models, Molecular; D057093:Orphan Nuclear Receptors; D012333:RNA, Messenger / Q000032:analysis; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry / Q000187:drug effects* / Q000235:genetics; D012503:Saponins / Q000494:pharmacology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
chemical_list: C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D001057:Apolipoproteins E; D004268:DNA-Binding Proteins; D008024:Ligands; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; D057093:Orphan Nuclear Receptors; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D012503:Saponins; D013755:Tetradecanoylphorbol Acetate