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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 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.

SUBMITTER: Gillis SP

PROVIDER: S-EPMC8196003 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Circadian dysfunction is a common attribute of many neurodegenerative diseases, most of which are associated with neuroinflammation. Circadian rhythm dysfunction has been associated with inflammation in the periphery, but the role of the core clock in neuroinflammation remains poorly understood. Here we demonstrate that Rev-erbα, a nuclear receptor and circadian clock component, is a mediator of microglial activation and neuroinflammation. We observed time-of-day oscillation in microglial immunoreactivity in the hippocampus, which was disrupted in Rev-erbα-/- mice. Rev-erbα deletion caused spontaneous microglial activation in the hippocampus and increased expression of proinflammatory transcripts, as well as secondary astrogliosis. Transcriptomic analysis of hippocampus from Rev-erbα-/- mice revealed a predominant inflammatory phenotype and suggested dysregulated NF-κB signaling. Primary Rev-erbα-/- microglia exhibited proinflammatory phenotypes and increased basal NF-κB activation. Chromatin immunoprecipitation revealed that Rev-erbα physically interacts with the promoter regions of several NF-κB-related genes in primary microglia. Loss of Rev-erbα in primary astrocytes had no effect on basal activation but did potentiate the inflammatory response to lipopolysaccharide (LPS). In vivo, Rev-erbα-/- mice exhibited enhanced hippocampal neuroinflammatory responses to peripheral LPS injection, while pharmacologic activation of Rev-erbs with the small molecule agonist SR9009 suppressed LPS-induced hippocampal neuroinflammation. Rev-erbα deletion influenced neuronal health, as conditioned media from Rev-erbα-deficient primary glial cultures exacerbated oxidative damage in cultured neurons. Rev-erbα-/- mice also exhibited significantly altered cortical resting-state functional connectivity, similar to that observed in neurodegenerative models. Our results reveal Rev-erbα as a pharmacologically accessible link between the circadian clock and neuroinflammation.

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

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