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Nuclear receptor REVERBα is a state-dependent regulator of liver energy metabolism

Hunter, AL; Pelekanou, CE; Adamson, A; Downton, P; Barron, NJ; Cornfield, T; Poolman, TM; ... Ray, DW; + view all (2020) Nuclear receptor REVERBα is a state-dependent regulator of liver energy metabolism. Proceedings of the National Academy of Sciences of the United States of America 10.1073/pnas.2005330117. (In press). Green open access

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Abstract

The nuclear receptor REVERBα is a core component of the circadian clock and proposed to be a dominant regulator of hepatic lipid metabolism. Using antibody-independent ChIP-sequencing of REVERBα in mouse liver, we reveal a high-confidence cistrome and define direct target genes. REVERBα-binding sites are highly enriched for consensus RORE or RevDR2 motifs and overlap with corepressor complex binding. We find no evidence for transcription factor tethering and DNA-binding domain-independent action. Moreover, hepatocyte-specific deletion of Reverbα drives only modest physiological and transcriptional dysregulation, with derepressed target gene enrichment limited to circadian processes. Thus, contrary to previous reports, hepatic REVERBα does not repress lipogenesis under basal conditions. REVERBα control of a more extensive transcriptional program is only revealed under conditions of metabolic perturbation (including mistimed feeding, which is a feature of the global Reverbα -/- mouse). Repressive action of REVERBα in the liver therefore serves to buffer against metabolic challenge, rather than drive basal rhythmicity in metabolic activity.

Type: Article
Title: Nuclear receptor REVERBα is a state-dependent regulator of liver energy metabolism
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1073/pnas.2005330117
Publisher version: https://doi.org/10.1073/pnas.2005330117
Language: English
Additional information: © 2020 the Author(s). Published by PNAS. This open access article is distributed under Creative Commons Attribution License 4.0 (http://creativecommons.org/licenses/by/4.0/).
Keywords: NR1D1, circadian clock, energy metabolism, liver, nuclear hormone receptor
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Structural and Molecular Biology
URI: https://discovery.ucl.ac.uk/id/eprint/10110985
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