title: Fatty acids derived from royal jelly are modulators of estrogen receptor functions.
abstract: Royal jelly (RJ) excreted by honeybees and used as a nutritional and medicinal agent has estrogen-like effects, yet the compounds mediating these effects remain unidentified. The possible effects of three RJ fatty acids (FAs) (10-hydroxy-2-decenoic-10H2DA, 3,10-dihydroxydecanoic-3,10DDA, sebacic acid-SA) on estrogen signaling was investigated in various cellular systems. In MCF-7 cells, FAs, in absence of estradiol (E(2)), modulated the estrogen receptor (ER) recruitment to the pS2 promoter and pS2 mRNA levels via only ERβ but not ERα, while in presence of E(2) FAs modulated both ERβ and ERα. Moreover, in presence of FAs, the E(2)-induced recruitment of the EAB1 co-activator peptide to ERα is masked and the E(2)-induced estrogen response element (ERE)-mediated transactivation is inhibited. In HeLa cells, in absence of E(2), FAs inhibited the ERE-mediated transactivation by ERβ but not ERα, while in presence of E(2), FAs inhibited ERE-activity by both ERβ and ERα. Molecular modeling revealed favorable binding of FAs to ERα at the co-activator-binding site, while binding assays showed that FAs did not bind to the ligand-binding pocket of ERα or ERβ. In KS483 osteoblasts, FAs, like E(2), induced mineralization via an ER-dependent way. Our data propose a possible molecular mechanism for the estrogenic activities of RJ's components which, although structurally entirely different from E(2), mediate estrogen signaling, at least in part, by modulating the recruitment of ERα, ERβ and co-activators to target genes.
authors.affiliation: Department of Biological Chemistry, Medical School, University of Athens, Athens, Greece. pmoutsatsou@med.uoa.gr
authors.forename: Paraskevi
authors.initials: P
authors.lastname: Moutsatsou
authors.forename: Zoi
authors.initials: Z
authors.lastname: Papoutsi
authors.forename: Eva
authors.initials: E
authors.lastname: Kassi
authors.forename: Nina
authors.initials: N
authors.lastname: Heldring
authors.forename: Chunyan
authors.initials: C
authors.lastname: Zhao
authors.forename: Anna
authors.initials: A
authors.lastname: Tsiapara
authors.forename: Eleni
authors.initials: E
authors.lastname: Melliou
authors.forename: George P
authors.initials: GP
authors.lastname: Chrousos
authors.forename: Ioanna
authors.initials: I
authors.lastname: Chinou
authors.forename: Andrey
authors.initials: A
authors.lastname: Karshikoff
authors.forename: Lennart
authors.initials: L
authors.lastname: Nilsson
authors.forename: Karin
authors.initials: K
authors.lastname: Dahlman-Wright
mesh_terms: D045744:Cell Line, Tumor; D047628:Estrogen Receptor alpha / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D008024:Ligands; D008954:Models, Biological; D008958:Models, Molecular; D010006:Osteoblasts / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism*; D013778:Tetrazolium Salts / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D015533:Transcriptional Activation; D020798:Two-Hybrid System Techniques; D000099219:Royal Jelly
chemical_list: D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D005227:Fatty Acids; D008024:Ligands; D011960:Receptors, Estrogen; D013778:Tetrazolium Salts; D013844:Thiazoles; D000099219:Royal Jelly; C022616:thiazolyl blue