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.

Oilseeds ameliorate metabolic parameters in male mice, while contained lignans inhibit 3T3-L1 adipocyte differentiation in vitro

“…Among these, the estrogen receptors ERa and ERb have been shown to be activated by the mammalian lignans ENL and END [31,54]. We here found that ER expression is induced in epididymal fat by sesame and flaxseeds, suggesting that their effect on fat mass deposition might have been produced through a mechanism that involves an estradiol-mimicking action.…”

“…However, in light of the most recent progresses in the area of the study of natural ligands for the ERs from nutritional sources, the term ''phytoestrogen'' appears to be inadequate or poorly representative of the actual activity of the lignans, when considering metabolic functions as functional targets. The reason is that it is becoming frequent to observe that the same molecules that bind and activate the ERs, also bind and activate other NRs that may play opposite actions on the regulation of target genes (i.e., PPARc) and activate NR cross-talks with outcomes that are not clear [31,56,57]. An example of a lignan that binds the PPARs is macelignan [58,59], which has been determined as a dual ligand for PPARa/c receptors.…”

“…The identified variables were as follows: the source of the lignans and other factors in the food, the doses of compounds in different preparations (extracts or whole grains), the time of intake, the targeted cohorts, the analyzed end-points and the methods of analysis [28]. Some mechanistic studies have also been performed identifying the lignans mainly as efficient antioxidants and phytoestrogenic compounds [29][30][31].…”

Dietary lariciresinol attenuates mammary tumor growth and reduces blood vessel density in human MCF‐7 breast cancer xenografts and carcinogen‐induced mammary tumors in rats

“…In the present study, no changes were observed in ERa expression levels of E2-stimulated MCF-7 tumors in response to several weeks' of lariciresinol administration. Interestingly, the relative binding affinity of enterolactone to both ERa and ERb is very low, 25,49,50 suggesting that enterolignans do not act as classical ER agonists in breast tumors in vivo. However, in vitro and in vivo, enterolactone has been shown to induce estrogen responsive reporter gene expression in tissue specific manner through ERs, and to promote some estrogen responsive genes and morphological changes in estrogen target tissues (e.g., uterus) in female mice.…”

“…However, in vitro and in vivo, enterolactone has been shown to induce estrogen responsive reporter gene expression in tissue specific manner through ERs, and to promote some estrogen responsive genes and morphological changes in estrogen target tissues (e.g., uterus) in female mice. 50 Thus, the ERa or ERb mediated effects of the dietary lignans and their metabolites acting systemically in normal endocrine target tissues cannot be excluded.…”