title: Diet-derived polyphenol metabolite enterolactone is a tissue-specific estrogen receptor activator.
abstract: Numerous dietary compounds can modify gene expression by binding to the members of the nuclear receptor superfamily of transcription factors. For example, dietary polyphenols, such as soy isoflavones genistein and daidzein, modulate the activity of the estrogen receptors (ERs)-alpha and ERbeta. An additional class of dietary polyphenols that modulate cellular signaling pathways are lignans, compounds that are common constituents of Western diets. In this study, we show that a metabolite of dietary lignans, enterolactone, at physiological concentrations, activates ER-mediated transcription in vitro with preference for ERalpha. The effects of enterolactone are mediated by the ER ligand binding domain and are susceptible to antiestrogen treatment. Furthermore, the affinity of enterolactone toward ERalpha, measured by a novel ligand binding assay, is augmented in cell culture conditions. Moreover, our results demonstrate for the first time that enterolactone has estrogenic activity in vivo. In transgenic estrogen-sensitive reporter mice, enterolactone induces tissue-specific estrogen-responsive reporter gene expression as well as promotes uterine stromal edema and expression of estrogen-responsive endogenous genes (CyclinD1 and Ki67). Taken together, our data show that enterolactone is a selective ER agonist inducing ER-mediated transcription both in vitro in different cell lines and in vivo in the mouse uterus.
authors.affiliation: Department of Biosciences and Nutrition at Novum, Karolinska Institute, Hälsovägen 7, SE-147 51 Huddinge, Sweden.
authors.forename: Pauliina
authors.initials: P
authors.lastname: Penttinen
authors.forename: Jan
authors.initials: J
authors.lastname: Jaehrling
authors.forename: Anastasios E
authors.initials: AE
authors.lastname: Damdimopoulos
authors.forename: José
authors.initials: J
authors.lastname: Inzunza
authors.forename: Josephine G
authors.initials: JG
authors.lastname: Lemmen
authors.forename: Paul
authors.initials: P
authors.lastname: van der Saag
authors.forename: Katarina
authors.initials: K
authors.lastname: Pettersson
authors.forename: Günter
authors.initials: G
authors.lastname: Gauglitz
authors.forename: Sari
authors.initials: S
authors.lastname: Mäkelä
authors.forename: Ingemar
authors.initials: I
authors.lastname: Pongratz
mesh_terms: D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000096:biosynthesis / Q000494:pharmacology; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D004032:Diet; D004965:Estrogen Antagonists / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000235:genetics; D047629:Estrogen Receptor beta / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects; D017930:Genes, Reporter; D006801:Humans; D008024:Ligands; D017705:Lignans / Q000096:biosynthesis / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D017434:Protein Structure, Tertiary / Q000502:physiology; D011960:Receptors, Estrogen / Q000819:agonists / Q000187:drug effects* / Q000378:metabolism*; D014018:Tissue Distribution; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D008024:Ligands; D017705:Lignans; D011960:Receptors, Estrogen; D015107:4-Butyrolactone; C029497:2,3-bis(3'-hydroxybenzyl)butyrolactone