RESUMO
Enterolactone (EL) is an enterolignan produced by gut microbiota from dietary plant lignans. Epidemiological and experimental studies suggest that EL and plant lignans may reduce the risk of breast and prostate cancer as well as cardiovascular disease. These effects are thought to at least in part involve modulation of estrogen receptor activity. Surprisingly little is known about the in vivo estrogenicity of EL. In the present study, we investigated the target tissues of EL, the genes affected by EL treatment, and the response kinetics. Following a single dose of EL, luciferase was significantly induced in reproductive and nonreproductive tissues of male and female 3xERE-luciferase mice, indicating estrogen-like activity. Microarray analysis revealed that EL regulated the expression of only 1% of 17ß-estradiol target genes in the uterus. The majority of these genes were traditional estrogen target genes, but also members of the circadian signaling pathway were affected. Kinetic analyses showed that EL undergoes rapid phase II metabolism and is efficiently excreted. In vivo imaging demonstrated that the estrogen response followed similar, fast kinetics. We conclude that EL activates estrogen signaling in both male and female mice and that the transient responses may be due to the fast metabolism of the compound. Lastly, EL may represent a link among diet, gut microbiota, and circadian signaling.
Assuntos
4-Butirolactona/análogos & derivados , Proteínas CLOCK/metabolismo , Relógios Circadianos/genética , Estrogênios/metabolismo , Lignanas/farmacologia , Fitoestrógenos/farmacologia , Transdução de Sinais/efeitos dos fármacos , 4-Butirolactona/sangue , 4-Butirolactona/farmacologia , Animais , Proteínas CLOCK/genética , Relógios Circadianos/efeitos dos fármacos , Estradiol/farmacologia , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Lignanas/sangue , Fígado/metabolismo , Luciferases/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Orquiectomia , Ovariectomia , Análise Serial de Proteínas , Distribuição Aleatória , Útero/metabolismoRESUMO
Together with the estrogen receptor (ER) alpha, estrogen receptor beta (ER beta ) mediates many of the physiological effects of estrogens. As ER beta is crucially involved in a variety of important physiological processes, its activity should be tightly regulated. ER beta regulation is achieved by hormone binding as well as by posttranslational modifications of the receptor. Furthermore, ER beta expression levels are under circadian control and can be regulated by DNA methylation of the ER beta promoter region. There are also a number of factors that can interfere with ER beta activity, such as phytoestrogens, endocrine disruptive chemicals, and growth factors. In this article, we outline different mechanisms of ER beta regulation and how they are implicated in various diseases. We also discuss how these insights might help to specifically target ER beta in drug design.
Assuntos
Receptor beta de Estrogênio/genética , Receptor beta de Estrogênio/metabolismo , Neoplasias/patologia , Processamento Alternativo , Metilação de DNA , Regulação Neoplásica da Expressão Gênica , Humanos , Modelos Biológicos , Neoplasias/genética , Neoplasias/metabolismo , Fitoestrógenos/metabolismo , Ligação Proteica , Processamento de Proteína Pós-TraducionalRESUMO
Transcriptional control of hypothalamic thyrotropin-releasing hormone (TRH) integrates central regulation of the hypothalamo-hypophyseal-thyroid axis and hence thyroid hormone (triiodothyronine (T(3))) homeostasis. The two beta thyroid hormone receptors, TRbeta1 and TRbeta2, contribute to T(3) feedback on TRH, with TRbeta1 having a more important role in the activation of TRH transcription. How TRbeta1 fulfils its role in activating TRH gene transcription is unknown. By using a yeast two-hybrid screening of a mouse hypothalamic complementary DNA library, we identified a novel partner for TRbeta1, hepatitis virus B X-associated protein 2 (XAP2), a protein first identified as a co-chaperone protein. TR-XAP2 interactions were TR isoform specific, being observed only with TRbeta1, and were enhanced by T(3) both in yeast and mammalian cells. Furthermore, small inhibitory RNA-mediated knockdown of XAP2 in vitro affected the stability of TRbeta1. In vivo, siXAP2 abrogated specifically TRbeta1-mediated (but not TRbeta2) activation of hypothalamic TRH transcription. This study provides the first in vivo demonstration of a regulatory, physiological role for XAP2.