Correction: Estrogen Signalling and the Metabolic Syndrome: Targeting the Hepatic Estrogen Receptor Alpha Action.
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ABSTRACT:
SUBMITTER: Matic M
PROVIDER: S-EPMC6583955 | biostudies-literature | 2019
REPOSITORIES: biostudies-literature
Publications
Correction: Estrogen Signalling and the Metabolic Syndrome: Targeting the Hepatic Estrogen Receptor Alpha Action.
Matic Marko M Bryzgalova Galyna G Gao Hui H Antonson Per P Humire Patricia P Omoto Yoko Y Portwood Neil N Pramfalk Camilla C Efendic Suad S Berggren Per-Olof PO Gustafsson Jan-Åke JÅ Dahlman-Wright Karin K
PloS one 20190619 6
[This corrects the article DOI: 10.1371/journal.pone.0057458.]. ...[more]
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Project description:An increasing body of evidence now links estrogenic signalling with the metabolic syndrome (MS). Despite the beneficial estrogenic effects in reversing some of the MS symptoms, the underlying mechanisms remain largely undiscovered. We have previously shown that total estrogen receptor alpha (ER?) knockout (KO) mice exhibit hepatic insulin resistance. To determine whether liver-selective ablation of ER? recapitulates metabolic phenotypes of ERKO mice we generated a liver-selective ER?KO mouse model, LERKO. We demonstrate that LERKO mice have efficient reduction of ER? selectively within the liver. However, LERKO and wild type control mice do not differ in body weight, and have a comparable hormone profile as well as insulin and glucose response, even when challenged with a high fat diet. Furthermore, LERKO mice display very minor changes in their hepatic transcript profile. Collectively, our findings indicate that hepatic ER? action may not be the responsible factor for the previously identified hepatic insulin resistance in ER?KO mice.
| S-EPMC3581463 | biostudies-literature
Project description:We have previously shown that total estrogen receptor alpha (ERalpha knockout (KO) mice exhibit hepatic insulin resistance. To investigate the contribution of hepatic ERalpha action for the observed phenotype, we established a liver-selective ERalphaKO mouse model, LERKO. We demonstrate that LERKO mice have efficient reduction of ERalpha selectively within the liver. However, LERKO and wild type control mice do not differ in body weight, and have a comparable hormone profile as well as insulin and glucose response, even when challenged with a high fat diet. Furthermore, LERKO mice display very minor changes in their hepatic transcript profile. Collectively, our findings indicate that hepatic ERalpha action may not be the initiating factor for the previously identified hepatic insulin resistance in ERalphaKO mice. We have previously shown that total estrogen receptor alpha (ERalpha knockout (KO) mice exhibit hepatic insulin resistance. To investigate the contribution of hepatic ERalpha action for the observed phenotype, we established a liver-selective ERalphaKO mouse model, LERKO. Using microarray analysis, we compared the hepatic transcriptional profile of LERKO vs control mice.
2012-12-01 | E-GEOD-36514 | biostudies-arrayexpress
Project description:We have previously shown that total estrogen receptor alpha (ERalpha knockout (KO) mice exhibit hepatic insulin resistance. To investigate the contribution of hepatic ERalpha action for the observed phenotype, we established a liver-selective ERalphaKO mouse model, LERKO. We demonstrate that LERKO mice have efficient reduction of ERalpha selectively within the liver. However, LERKO and wild type control mice do not differ in body weight, and have a comparable hormone profile as well as insulin and glucose response, even when challenged with a high fat diet. Furthermore, LERKO mice display very minor changes in their hepatic transcript profile. Collectively, our findings indicate that hepatic ERalpha action may not be the initiating factor for the previously identified hepatic insulin resistance in ERalphaKO mice.
2012-12-01 | GSE36514 | GEO
Project description:BackgroundFetal neuroendocrine maturation in late gestation is critical for maintenance of fetal homeostasis, growth, and readiness for birth. Sheep express estrogen receptors (ERs) in various brain regions. However, little is known about the regulation of ER-alpha and ER-beta in the ovine brain prenatally.ObjectiveThe present study was designed to test the hypothesis that the expression of ER is influenced by circulating estrogens in the late-gestation sheep fetus.MethodsSix chronically-catheterized twin fetal sheep were treated with vehicle or the ER blocker ICI 182,780 i.c.v. (0.25 microg/day). Fetuses were sacrificed 6-14 days after surgery and start of infusion. Brain regions were rapidly isolated and snap-frozen for later extraction of mRNA and protein. ER-alpha and ER-beta mRNA was measured using real-time PCR and protein was measured using Western blot.ResultsTreatment with ICI 182,780 increased ER-alpha mRNA, especially in cerebellum and hippocampus. There were no changes in ER-alpha protein and no changes in ER-beta at either the mRNA or protein level.ConclusionExpression of ER-alpha is influenced by endogenous estrogens in the ovine fetal brain.
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Project description:Menopause is associated with dyslipidemia and an increased risk of cardiovascular disease, the underlying mechanism of dyslipidemia is attributed to an insufficiency of estrogen. In this study, we find that estrogen mediates an atherosclerotic-protective action via estrogen receptor alpha/SREBP-1 signaling. Increased lipid accumulation and low-density lipoprotein (LDL)-uptake in HepG2 cells and THP-1 macrophages were induced by treatment of mixed hyperlipidemic serum from postmenopausal women; 17β-estradiol [estrogen (E2)] (10 nM) administration significantly improved hyperlipidemic profiles, relieved fatty-liver damage and attenuated the plaque area in the heart chamber of high-fat diet (HFD)-fed ovariectomized (OVX) ApoE -/ - mice. Expression of sterol regulatory element-binding protein (SREBP)-1 mRNA of circulating leukocytes in postmenopausal women was strongly correlated to the serum E2 level. Exploration of data from the Gene Expression Profiling Interactive Analysis (GEPIA) database revealed that expression of SREBP-1 protein correlated to expression of estrogen receptor (ESR)α protein in the liver, blood and in normal tissue. Genetic overexpression/inhibition of ESRα resulted in increased/decreased SREBP-1 expression as well as attenuated/deteriorated lipid deposition in vitro. An inhibitor of the protein kinase B/mammalian target of rapamycin (AKT/mTOR) pathway, AZD8055, abolished ESRα-induced SREBP-1 expression in HepG2 cells. Moreover, E2 and statin co-treatment significantly reduced lipid accumulation in vitro and hindered the progression of atherosclerosis and fatty-liver damage in OVX ApoE -/ - mice. Collectively, our results suggest that estrogen could exerted its atherosclerotic-protective action via ESRα/SREBP-1 signaling. E2 might enhance the cellular sensitivity of statins and could be used as a novel therapeutic strategy against atherosclerotic disorders in postmenopausal women.
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Project description:Estrogens play a pivotal role in the control of female reproductive function. Recent studies using primate GnRH neurons derived from embryonic nasal placode indicate that 17?-estradiol (E(2)) causes a rapid stimulatory action. E(2) (1nM) stimulates firing activity and intracellular calcium ([Ca(2+)](i)) oscillations of primate GnRH neurons within a few min. E(2) also stimulates GnRH release within 10min. However, the classical estrogen receptors, ER? and ER?, do not appear to play a role in E(2)-induced [Ca(2+)](i) oscillations or GnRH release, as the estrogen receptor antagonist, ICI 182,780, failed to block these responses. Rather, this rapid E(2) action is, at least in part, mediated by a G-protein coupled receptor GPR30. In the present study we further investigate the role of ER? and ER? in the rapid action of E(2) by knocking down cellular ER? and ER? by transfection of GnRH neurons with specific siRNA for rhesus monkey ER? and ER?. Results indicate that cellular knockdown of ER? and ER? failed to block the E(2)-induced changes in [Ca(2+)](i) oscillations. It is concluded that neither ER? nor ER? is required for the rapid action of E(2) in primate GnRH neurons.
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Project description:Estrogen receptor alpha (ER alpha) is a ligand-regulated transcription factor with a broad range of physiological functions and one of the most important classifiers in breast cancer. MicroRNAs (miRNAs) are small noncoding RNAs that have emerged as important regulators of gene expression in a plethora of physiological and pathological processes. Upon binding the 3' untranslated region (UTR) of target mRNAs, miRNAs typically reduce their stability and/or translation. The ER alpha mRNA has a long 3' UTR of about 4.3 kb which has been reported to reduce mRNA stability and which bears evolutionarily conserved miRNA target sites, suggesting that it might be regulated by miRNAs. We have performed a comprehensive and systematic assessment of the regulatory role of all miRNAs that are predicted to target the 3' UTR of the ER alpha mRNA. We found that miR-22 represses ER alpha expression most strongly and by directly targeting the ER alpha mRNA 3' UTR. Of the three predicted miR-22 target sites in the 3' UTR, the evolutionarily conserved one is the primary target. miR-22 overexpression leads to a reduction of ER alpha levels, at least in part by inducing mRNA degradation, and compromises estrogen signaling, as exemplified by its inhibitory impact on the ER alpha-dependent proliferation of breast cancer cells.
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Project description:Recent studies showed the potential linkage of estrogen/estrogen receptor signaling with bladder tumorigenesis, yet detailed mechanisms remain elusive. Here we found a new potential therapy with the combination of Bacillus Calmette-Guerin (BCG) and the anti-estrogen ICI 182,780 led to better suppression of bladder cancer (BCa) than BCG alone. Mechanism dissection found ICI 182,780 could promote BCG attachment/internalization to the BCa cells through increased integrin-α5β1 expression and IL-6 release, which may enhance BCG-induced suppression of BCa cell growth via recruiting more monocytes/macrophages to BCa cells and increased TNF-α release. Consistently, in vivo studies found ICI 182,780 could potentiate the anti-BCa effects of BCG in the carcinogen-induced mouse BCa models. Together, these in vitro and in vivo results suggest that combining BCG with anti-estrogen may become a new therapeutic approach with better efficacy to suppress BCa progression and recurrence.
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Project description:Estrogen clearly prevents osteoporotic bone loss by attenuating bone resorption. The molecular basis of how this is accomplished, however, remains elusive. Here we report a critical role of osteoclastic ERa in mediating estrogen action on bone in females. We selectively ablated ERa in differentiated osteoclasts (ERa dOc/dOc). ERa dOc/dOc females, but not males, exhibited clear trabecular bone loss, similar to the osteoporotic bone phenotype in post-menopausal women. Recovery of bone loss by estrogen treatment of the ovariectomized ERa dOc/dOc females was ineffective in the trabecular areas of the long bones and lumbar vertebral bodies. Osteoclastic apoptosis, induced by estrogen, occurred simultaneously with up-regulation of Fas ligand (FasL) expression in intact trabecular bones of ERa +/+mice, but not in ERa dOc/dOc mice. ERa was also required for similar effects of estrogen and tamoxifen in cultured osteoclasts. These findings suggest that the osteoprotective actions of estrogen and SERMS are mediated at least in part through osteoclastic ERa in trabecular bone; and the life span of mature osteoclasts is regulated through activation of the Fas/FasL system. Keywords: Study about estrogen response of osteoclast-specific estrogen receptor alpha mice
2007-06-01 | GSE7798 | GEO
Project description:Many endocrine disrupting chemicals (EDCs) adversely impact estrogen signaling by interacting with two estrogen receptors (ERs): ER? and ER?. Though the receptors have similar ligand binding and DNA binding domains, ER? and ER? have some unique properties in terms of ligand selectivity and target gene regulation. EDCs that target ER signaling can modify genomic and nongenomic ER activity through direct interactions with ERs, indirectly through transcription factors such as the aryl hydrocarbon receptor (AhR), or through modulation of metabolic enzymes that are critical for normal estrogen synthesis and metabolism. Many EDCs act through multiple mechanisms as exemplified by chemicals that bind both AhR and ER, such as 3-methylcholanthrene. Other EDCs that target ER signaling include phytoestrogens, bisphenolics, and organochlorine pesticides, and many alter normal ER signaling through multiple mechanisms. EDCs can also display tissue-selective ER agonist and antagonist activities similar to selective estrogen receptor modulators (SERMs) designed for pharmaceutical use. Thus, biological effects of EDCs need to be carefully interpreted because EDCs can act through complex tissue-selective modulation of ERs and other signaling pathways in vivo. Current requirements by the U.S. Environmental Protection Agency require some in vitro and cell-based assays to identify EDCs that target ER signaling through direct and metabolic mechanisms. Additional assays may be useful screens for identifying EDCs that act through alternative mechanisms prior to further in vivo study.
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