REVERBa couples the circadian clock to hepatic glucocorticoid action

Research output: Contribution to journalArticle

  • External authors:
  • Giorgio Caratti
  • Donghwan Kim
  • Ping Wang
  • Ryan M Vonslow
  • Nicola Begley
  • Abigail J Tetley
  • Joanna L Woodburn
  • Marie Pariollaud
  • Zhenguang Zhang
  • Louise M Ince
  • Matthew Baxter
  • Toryn M Poolman
  • Dion A Daniels
  • David R Stirling
  • Chad Brocker
  • Frank Gonzalez
  • David A Bechtold
  • Magnus Rattray
  • Laura C Matthews
  • David W Ray

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.

Bibliographical metadata

Original languageEnglish
Pages (from-to)4454-4471
JournalThe Journal of clinical investigation
Volume128
Issue number10
Early online date4 Sep 2018
DOIs
StatePublished - 1 Oct 2018