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Nighttime light exposure enhances Rev-erb?-targeting microRNAs and contributes to hepatic steatosis.

ABSTRACT: OBJECTIVE:The exposure to artificial light at night (ALAN) disrupts the biological rhythms and has been associated with the development of metabolic syndrome. MicroRNAs (miRNAs) display a critical role in fine-tuning the circadian system and energy metabolism. In this study, we aimed to assess whether altered miRNAs expression in the liver underlies metabolic disorders caused by disrupted biological rhythms. RESULTS:We found that C3H/HePas mice exposed to ALAN developed obesity, and hepatic steatosis, which was paralleled by decreased expression of Rev-erb? and up-regulation of its lipogenic targets ACL and FAS in liver. Furthermore, the expression of Rev-erb?-targeting miRNAs, miR-140-5p, 185-5p, 326-5p and 328-5p were increased in this group. Consistently, overexpression of these miRNAs in primary hepatocytes reduced Rev-erb? expression at the mRNA and protein levels. Importantly, overexpression of Rev-erb?-targeting miRNAs increased mRNA levels of Acly and Fasn. CONCLUSION:Thus, altered miRNAs profile is an important mechanism underlying the disruption of the peripheral clock caused by exposure to ALAN, which could lead to hepatic steatosis.

SUBMITTER: Borck PC

PROVIDER: S-EPMC6145802 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Nighttime light exposure enhances Rev-erbα-targeting microRNAs and contributes to hepatic steatosis.

Borck Patricia C PC Batista Thiago M TM Vettorazzi Jean F JF Soares Gabriela M GM Lubaczeuski Camila C Guan Dongyin D Boschero Antonio C AC Vieira Elaine E Lazar Mitchell A MA Carneiro Everardo M EM

Metabolism: clinical and experimental 20180508

<h4>Objective</h4>The exposure to artificial light at night (ALAN) disrupts the biological rhythms and has been associated with the development of metabolic syndrome. MicroRNAs (miRNAs) display a critical role in fine-tuning the circadian system and energy metabolism. In this study, we aimed to assess whether altered miRNAs expression in the liver underlies metabolic disorders caused by disrupted biological rhythms.<h4>Results</h4>We found that C3H/HePas mice exposed to ALAN developed obesity, a ...[more]

PMID: 29751019

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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.

Dataset Information

Nighttime light exposure enhances Rev-erb?-targeting microRNAs and contributes to hepatic steatosis.

Publications

Nighttime light exposure enhances Rev-erbα-targeting microRNAs and contributes to hepatic steatosis.

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