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Estrogen Deficiency Promotes Hepatic Steatosis via a Glucocorticoid Receptor-Dependent Mechanism in Mice
Glucocorticoids (GCs) are master regulators of systemic metabolism. Intriguingly, Cushing’s syndrome, a disorder of excessive GCs, phenocopies several menopause-induced metabolic pathologies. Here, we show that the glucocorticoid receptor (GR) drives steatosis in hypogonadal female mice because hepa...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5875726/ https://www.ncbi.nlm.nih.gov/pubmed/29514097 http://dx.doi.org/10.1016/j.celrep.2018.02.041 |
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author | Quinn, Matthew A. Xu, Xiaojiang Ronfani, Melania Cidlowski, John A. |
author_facet | Quinn, Matthew A. Xu, Xiaojiang Ronfani, Melania Cidlowski, John A. |
author_sort | Quinn, Matthew A. |
collection | PubMed |
description | Glucocorticoids (GCs) are master regulators of systemic metabolism. Intriguingly, Cushing’s syndrome, a disorder of excessive GCs, phenocopies several menopause-induced metabolic pathologies. Here, we show that the glucocorticoid receptor (GR) drives steatosis in hypogonadal female mice because hepatocyte-specific GR knockout mice are refractory to developing ovariectomy-induced steatosis. Intriguingly, transcriptional profiling revealed that ovariectomy elicits hepatic GC hypersensitivity globally. Hypogonadism-induced GC hypersensitivity results from a loss of systemic but not hepatic estrogen (E2) signaling, given that hepatocyte-specific E2 receptor deletion does not confer GC hypersensitivity. Mechanistically, enhanced chromatin recruitment and ligand-dependent hyperphosphorylation of GR underlie ovariectomy-induced glucocorticoid hypersensitivity. The dysregulated glucocorticoid-mediated signaling present in hypogonadal females is a product of increased follicle-stimulating hormone (FSH) production because FSH treatment in ovary-intact mice recapitulates glucocorticoid hypersensitivity similar to hypogonadal female mice. Our findings uncover a regulatory axis between estradiol, FSH, and hepatic glucocorticoid receptor signaling that, when disrupted, as in menopause, promotes hepatic steatosis. |
format | Online Article Text |
id | pubmed-5875726 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
record_format | MEDLINE/PubMed |
spelling | pubmed-58757262018-03-29 Estrogen Deficiency Promotes Hepatic Steatosis via a Glucocorticoid Receptor-Dependent Mechanism in Mice Quinn, Matthew A. Xu, Xiaojiang Ronfani, Melania Cidlowski, John A. Cell Rep Article Glucocorticoids (GCs) are master regulators of systemic metabolism. Intriguingly, Cushing’s syndrome, a disorder of excessive GCs, phenocopies several menopause-induced metabolic pathologies. Here, we show that the glucocorticoid receptor (GR) drives steatosis in hypogonadal female mice because hepatocyte-specific GR knockout mice are refractory to developing ovariectomy-induced steatosis. Intriguingly, transcriptional profiling revealed that ovariectomy elicits hepatic GC hypersensitivity globally. Hypogonadism-induced GC hypersensitivity results from a loss of systemic but not hepatic estrogen (E2) signaling, given that hepatocyte-specific E2 receptor deletion does not confer GC hypersensitivity. Mechanistically, enhanced chromatin recruitment and ligand-dependent hyperphosphorylation of GR underlie ovariectomy-induced glucocorticoid hypersensitivity. The dysregulated glucocorticoid-mediated signaling present in hypogonadal females is a product of increased follicle-stimulating hormone (FSH) production because FSH treatment in ovary-intact mice recapitulates glucocorticoid hypersensitivity similar to hypogonadal female mice. Our findings uncover a regulatory axis between estradiol, FSH, and hepatic glucocorticoid receptor signaling that, when disrupted, as in menopause, promotes hepatic steatosis. 2018-03-06 /pmc/articles/PMC5875726/ /pubmed/29514097 http://dx.doi.org/10.1016/j.celrep.2018.02.041 Text en http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Article Quinn, Matthew A. Xu, Xiaojiang Ronfani, Melania Cidlowski, John A. Estrogen Deficiency Promotes Hepatic Steatosis via a Glucocorticoid Receptor-Dependent Mechanism in Mice |
title | Estrogen Deficiency Promotes Hepatic Steatosis via a Glucocorticoid Receptor-Dependent Mechanism in Mice |
title_full | Estrogen Deficiency Promotes Hepatic Steatosis via a Glucocorticoid Receptor-Dependent Mechanism in Mice |
title_fullStr | Estrogen Deficiency Promotes Hepatic Steatosis via a Glucocorticoid Receptor-Dependent Mechanism in Mice |
title_full_unstemmed | Estrogen Deficiency Promotes Hepatic Steatosis via a Glucocorticoid Receptor-Dependent Mechanism in Mice |
title_short | Estrogen Deficiency Promotes Hepatic Steatosis via a Glucocorticoid Receptor-Dependent Mechanism in Mice |
title_sort | estrogen deficiency promotes hepatic steatosis via a glucocorticoid receptor-dependent mechanism in mice |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5875726/ https://www.ncbi.nlm.nih.gov/pubmed/29514097 http://dx.doi.org/10.1016/j.celrep.2018.02.041 |
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