REVERBa couples the circadian clock to hepatic glucocorticoid action

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.

Cardiomyocyte transcription is controlled by combined mineralocorticoid receptor and circadian clock signalling

“…BMAL-CLOCK proteins are in turn inhibited by PER/CRY to establish the periodicity of the system. Other circadian genes -that is Npas2, casein kinase 1ε (CsnK1ε) and ReverbA -reinforce 'time keeping' of the clock (Caratti et al 2018). Many circadian clock proteins are transcription factors and directly regulate the rhythmic expression of thousands of genes via E-box response elements in target gene promoters (Durgan & Young 2010).…”

The importance of being rhythmic: Living in harmony with your body clocks

“…202 Furthermore, recent evidence suggests that timed exercise has the potential to improve metabolic characteristics. [39][40][41][42]187,190 Photomultiplier tube-based measurements are sued to conduct population analysis of cellular rhythms (upper schema), 210 taken into account when administrating metformin, 206 lipid lowering drugs, 127 inflammatory drugs targeting the glucocorticoid receptor 122,207 and many other therapeutic agents. 205 Indeed, liver clocks have important impact on the response to numerous medications, which should certainly be F I G U R E 3 Clock in the dish: approaches for molecular in-vitro studies of human peripheral oscillators.…”

“…Following lentiviral transduction, cells are synchronized in vitro by various stimuli and subjected to circadian bioluminescence recording during several days. [39][40][41][42]187,190 Photomultiplier tube-based measurements are sued to conduct population analysis of cellular rhythms (upper schema), 210 taken into account when administrating metformin, 206 lipid lowering drugs, 127 inflammatory drugs targeting the glucocorticoid receptor 122,207 and many other therapeutic agents.…”

“…Of note, local tissue oxygenation has been recently reported to modulate the cellular clockwork via HIF1α signalling. 122 Liver-specific Bmal1KO leads to reduced lipid accumulation in hepatic cells via increased mRNA methylation, in particular of PPARα. Indeed, mice with diverse clock impairments develop hyperglycemia, hypoinsulinemia and glucose intolerance.…”

“…121 In the liver, REV-ERBα couples glucocorticoid signalling to energy metabolism via binding of the hepatocyte nuclear transcription factors HNF4A/HNF6. 122 Liver-specific Bmal1KO leads to reduced lipid accumulation in hepatic cells via increased mRNA methylation, in particular of PPARα. In turn, knockdown of the m6A methyltransferase | 5 of 14…”