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Endocrinology Vol. 141, No. 10 3799-3806
Copyright © 2000 by The Endocrine Society

ARTICLES

Circadian and Glucocorticoid Regulation of Rev-erb{alpha} Expression in Liver1

Inés Pineda Torra, Vladimir Tsibulsky, Franck Delaunay, Régis Saladin, Vincent Laudet, Jean-Charles Fruchart, Vladimir Kosykh and Bart Staels

U.325 INSERM, Département d’Athérosclérose (I.P.T., V.T., R.S., J.-C.F., B.S.), Institut Pasteur, 59019 Lille, and the Faculté de Pharmacie, Université de Lille II, 59006 Lille, France; CNRS UMR 5665 (F.D., V.L.), Ecole Normale Supérieure de Lyon, 69364 Lyon, France; and Institute of Experimental Cardiology (V.K.), Russian Cardiology Complex, Moscow, Russia

Address all correspondence and requests for reprints to: Bart Staels, U.325 INSERM, Institut Pasteur de Lille, 1 Rue Calmette BP245, 59019 Lille, France. E-mail: Bart Staels{at}pasteur-lille.fr

Rev-erb{alpha} [NR1D1], a member of the nuclear receptor superfamily, is an orphan receptor that constitutively represses gene transcription. Rev-erb{alpha} has been shown to play a role in myocyte differentiation and to be induced during adipogenesis. Furthermore, Rev-erb{alpha} is a regulator of lipoprotein metabolism. It was recently shown that Rev-erb{alpha} messenger RNA (mRNA) levels oscillate diurnally in rat liver. Here, we report that the circadian rhythm of Rev-erb{alpha} in liver is maintained in primary cultures of rat hepatocytes. Because glucocorticoids have been shown to regulate other transcription factors with circadian expression, it was furthermore examined whether hepatic Rev-erb{alpha} expression is also regulated by glucocorticoids. Treatment of rats with dexamethasone resulted in a decrease of Rev-erb{alpha} mRNA levels by 70% after 6 h. Furthermore, dexamethasone decreased Rev-erb{alpha} expression in rat primary hepatocytes in a dose-dependent fashion. This effect was mediated by the glucocorticoid receptor because simultaneous addition of the glucocorticoid antagonist RU486 prevented the decrease in Rev-erb{alpha} mRNA levels by dexamethasone. Protein synthesis inhibition with cycloheximide markedly induced Rev-erb{alpha} mRNA levels; however, this induction was reduced by dexamethasone supplementation in both rat and human primary hepatocytes. Treatment with actinomycin D blocked the repression of Rev-erb{alpha} expression by dexamethasone in rat hepatocytes, suggesting that glucocorticoids regulate Rev-erb{alpha} expression at the transcriptional level. Transient transfection experiments further indicated that Rev-erb{alpha} promoter activity is repressed by dexamethasone in the presence 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.




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