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REVERBa couples the circadian clock to hepatic glucocorticoid action
Giorgio Caratti, … , Laura C. Matthews, David W. Ray
Giorgio Caratti, … , Laura C. Matthews, David W. Ray
Published September 4, 2018
Citation Information: J Clin Invest. 2018;128(10):4454-4471. https://doi.org/10.1172/JCI96138.
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Research Article Endocrinology Metabolism

REVERBa couples the circadian clock to hepatic glucocorticoid action

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Abstract

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.

Authors

Giorgio Caratti, Mudassar Iqbal, Louise Hunter, Donghwan Kim, Ping Wang, Ryan M. Vonslow, Nicola Begley, Abigail J. Tetley, Joanna L. Woodburn, Marie Pariollaud, Robert Maidstone, Ian J. Donaldson, Zhenguang Zhang, Louise M. Ince, Gareth Kitchen, Matthew Baxter, Toryn M. Poolman, Dion A. Daniels, David R. Stirling, Chad Brocker, Frank Gonzalez, Andrew S.I. Loudon, David A. Bechtold, Magnus Rattray, Laura C. Matthews, David W. Ray

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Figure 1

GCs induce tissue-specific transcriptomes.

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GCs induce tissue-specific transcriptomes.
(A) GR immunohistochemistry i...
(A) GR immunohistochemistry in lung and liver at ZT8 (Day) and ZT20 (Night). GR expression is shown in brown; nuclei are blue. Br, bronchioles. C57BL/6 mice were given vehicle or 1 mg/kg i.p. dex at ZT6 (1 pm, day) or ZT18 (1 am, night) and culled 2 hours later, and lung and liver were analyzed by RNA-Seq. (B) Venn diagram depicting all GC-regulated genes identified byDESeq2 (n = 2 per group, >2-fold change to vehicle control, <0.05 FDR). Lung- and liver-specific targets are indicated, with gene ontology terms for each group listed below. SRP, signal recognition particle.

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