Loss of the transcriptional repressor Rev-erbα upregulates metabolism and proliferation in cultured mouse embryonic fibroblasts

Abstract The transcriptional repressor Rev-erbα is known to down-regulate fatty acid metabolism and gluconeogenesis gene expression. In animal models, disruption of Rev-erbα results in global changes in exercise performance, oxidative capacity, and blood glucose levels. However, the complete extent...

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Autores principales:	Sean P. Gillis, Hongwei Yao, Salu Rizal, Hajime Maeda, Julia Chang, Phyllis A. Dennery
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/81035a3f2c70403c89406b56f3664cac
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spelling	oai:doaj.org-article:81035a3f2c70403c89406b56f3664cac2021-12-02T17:47:35ZLoss of the transcriptional repressor Rev-erbα upregulates metabolism and proliferation in cultured mouse embryonic fibroblasts10.1038/s41598-021-91516-52045-2322https://doaj.org/article/81035a3f2c70403c89406b56f3664cac2021-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-91516-5https://doaj.org/toc/2045-2322Abstract The transcriptional repressor Rev-erbα is known to down-regulate fatty acid metabolism and gluconeogenesis gene expression. In animal models, disruption of Rev-erbα results in global changes in exercise performance, oxidative capacity, and blood glucose levels. However, the complete extent to which Rev-erbα-mediated transcriptional repression of metabolism impacts cell function remains unknown. We hypothesized that loss of Rev-erbα in a mouse embryonic fibroblast (MEF) model would result in global changes in metabolism. MEFs lacking Rev-erbα exhibited a hypermetabolic phenotype, demonstrating increased levels of glycolysis and oxidative phosphorylation. Rev-erbα deletion increased expression of hexokinase II, transketolase, and ribose-5-phosphate isomerase genes involved in glycolysis and the pentose phosphate pathway (PPP), and these effects were not mediated by the transcriptional activator BMAL1. Upregulation of oxidative phosphorylation was not accompanied by an increase in mitochondrial biogenesis or numbers. Rev-erbα repressed proliferation via glycolysis, but not the PPP. When treated with H2O2, cell viability was reduced in Rev-erbα knockout MEFs, accompanied by increased ratio of oxidized/reduced NADPH, suggesting that perturbation of the PPP reduces capacity to mount an antioxidant defense. These findings uncover novel mechanisms by which glycolysis and the PPP are modulated through Rev-erbα, and provide new insights into how Rev-erbα impacts proliferation.Sean P. GillisHongwei YaoSalu RizalHajime MaedaJulia ChangPhyllis A. DenneryNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Sean P. Gillis Hongwei Yao Salu Rizal Hajime Maeda Julia Chang Phyllis A. Dennery Loss of the transcriptional repressor Rev-erbα upregulates metabolism and proliferation in cultured mouse embryonic fibroblasts
description	Abstract The transcriptional repressor Rev-erbα is known to down-regulate fatty acid metabolism and gluconeogenesis gene expression. In animal models, disruption of Rev-erbα results in global changes in exercise performance, oxidative capacity, and blood glucose levels. However, the complete extent to which Rev-erbα-mediated transcriptional repression of metabolism impacts cell function remains unknown. We hypothesized that loss of Rev-erbα in a mouse embryonic fibroblast (MEF) model would result in global changes in metabolism. MEFs lacking Rev-erbα exhibited a hypermetabolic phenotype, demonstrating increased levels of glycolysis and oxidative phosphorylation. Rev-erbα deletion increased expression of hexokinase II, transketolase, and ribose-5-phosphate isomerase genes involved in glycolysis and the pentose phosphate pathway (PPP), and these effects were not mediated by the transcriptional activator BMAL1. Upregulation of oxidative phosphorylation was not accompanied by an increase in mitochondrial biogenesis or numbers. Rev-erbα repressed proliferation via glycolysis, but not the PPP. When treated with H2O2, cell viability was reduced in Rev-erbα knockout MEFs, accompanied by increased ratio of oxidized/reduced NADPH, suggesting that perturbation of the PPP reduces capacity to mount an antioxidant defense. These findings uncover novel mechanisms by which glycolysis and the PPP are modulated through Rev-erbα, and provide new insights into how Rev-erbα impacts proliferation.
format	article
author	Sean P. Gillis Hongwei Yao Salu Rizal Hajime Maeda Julia Chang Phyllis A. Dennery
author_facet	Sean P. Gillis Hongwei Yao Salu Rizal Hajime Maeda Julia Chang Phyllis A. Dennery
author_sort	Sean P. Gillis
title	Loss of the transcriptional repressor Rev-erbα upregulates metabolism and proliferation in cultured mouse embryonic fibroblasts
title_short	Loss of the transcriptional repressor Rev-erbα upregulates metabolism and proliferation in cultured mouse embryonic fibroblasts
title_full	Loss of the transcriptional repressor Rev-erbα upregulates metabolism and proliferation in cultured mouse embryonic fibroblasts
title_fullStr	Loss of the transcriptional repressor Rev-erbα upregulates metabolism and proliferation in cultured mouse embryonic fibroblasts
title_full_unstemmed	Loss of the transcriptional repressor Rev-erbα upregulates metabolism and proliferation in cultured mouse embryonic fibroblasts
title_sort	loss of the transcriptional repressor rev-erbα upregulates metabolism and proliferation in cultured mouse embryonic fibroblasts
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/81035a3f2c70403c89406b56f3664cac
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Loss of the transcriptional repressor Rev-erbα upregulates metabolism and proliferation in cultured mouse embryonic fibroblasts

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