Circadian and glucocorticoid regulation of Rev-erb alpha expression in liver

Rev-erb alpha [NR1D1], a member of the nuclear receptor superfamily, is an orphan receptor that constitutively represses gene transcription. Rev-erb a lpha has been shown to play a role in myocyte differentiation and to be ind uced during adipogenesis. Furthermore, Rev-erb alpha is a regulator of lipo protein metabolism. It was recently shown that Rev-erb alpha messenger RNA (mRNA) levels oscillate diurnally in rat liver. Here, we report that the ci rcadian rhythm of Rev-erb alpha in liver is maintained in primary cultures of rat hepatocytes. Because glucocorticoids have been shown to regulate oth er transcription factors with circadian expression, it was furthermore exam ined whether hepatic Rev-erb alpha expression is also regulated by glucocor ticoids. Treatment of rats with dexamethasone resulted in a decrease of Rev -erb alpha mRNA levels by 70% after 6 h. Furthermore, dexamethasone decreas ed Rev-erb alpha expression in rat primary hepatocytes in a dose-dependent fashion. This effect was mediated by the glucocorticoid receptor because si multaneous addition of the glucocorticoid antagonist RU486 prevented the de crease in Rev-erb alpha mRNA levels by dexamethasone. Protein synthesis inh ibition with cyclohexamide markedly induced Rev-erb alpha mRNA levels; howe ver, this induction was reduced by dexamethasone supplementation in both ra t and human primary hepatocytes. Treatment with actinomycin D blocked the r epression of Rev-erb alpha expression by dexamethasone in rat hepatocytes, suggesting that glucocorticoids regulate Rev-erb alpha expression at the tr anscriptional level. Transient transfection experiments further indicated t hat Rev-erb alpha promoter activity is repressed by dexamethasone in the pr esence of cotransfected glucocorticoid receptor. Taken together, these data demonstrate that Rev-erb alpha expression is under the control of both the circadian clock and glucocorticoids in the liver.