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J Clin Invest. 2018 Oct 1;128(10):4454-4471. doi: 10.1172/JCI96138. Epub 2018 Sep 4.

REVERBa couples the circadian clock to hepatic glucocorticoid action.

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Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Sciences Centre, and Specialist Medicine, Central Manchester Foundation Trust, Manchester, United Kingdom.
Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, USA.
Biopharmaceutical Molecular Discovery, GlaxoSmithKline, Medicines Research Centre, Stevenage, United Kingdom.
Leeds Institute of Cancer and Pathology, Faculty of Medicine and Health, University of Leeds, Leeds, United Kingdom.
Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, United Kingdom.


The glucocorticoid receptor (GR) is a major drug target in inflammatory disease. However, chronic glucocorticoid (GC) treatment leads to disordered energy metabolism, including increased weight gain, adiposity, and hepatosteatosis - all programs modulated by the circadian clock. We demonstrated that while antiinflammatory GC actions were maintained irrespective of dosing time, the liver was significantly more GC sensitive during the day. Temporal segregation of GC action was underpinned by a physical interaction of GR with the circadian transcription factor REVERBa and co-binding with liver-specific hepatocyte nuclear transcription factors (HNFs) on chromatin. REVERBa promoted efficient GR recruitment to chromatin during the day, acting in part by maintaining histone acetylation, with REVERBa-dependent GC responses providing segregation of carbohydrate and lipid metabolism. Importantly, deletion of Reverba inverted circadian liver GC sensitivity and protected mice from hepatosteatosis induced by chronic GC administration. Our results reveal a mechanism by which the circadian clock acts through REVERBa in liver on elements bound by HNF4A/HNF6 to direct GR action on energy metabolism.


Endocrinology; Metabolism; Transcription

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