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This version published online on March 23, 2006
Molecular Endocrinology, doi:10.1210/me.2006-0052
A more recent version of this article appeared on August 1, 2006
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Submitted on January 30, 2006
Accepted on March 15, 2006

Reciprocal regulation of BMAL1 and PPAR{alpha} defines a novel positive feedback loop in the rodent liver circadian clock

Laurence Canaple, Juliette Rambaud, Ouria Dkhissi-Benyahya°, Béatrice Rayet, Nguan Soon Tan, Liliane Michalik, Franck Delaunay, Walter Wahli, and Vincent Laudet*

*Structure and Evolution of Nuclear Receptors, CNRS UMR 5161, IFR 128 BioSciences Lyon-Gerland, Laboratoire de Biologie Moléculaire de la Cellule, Ecole Normale Supérieure, 46 allée d'Italie, 69364 Lyon cedex 07, France; ° INSERM U-371, Laboratoire Cerveau et Vision, IFR 19-UCBL, 18 avenue du Doyen Lépine, 69675 Bron, France; Université de Nice Sophia Antipolis CNRS FRE 2721 Bâtiment de Sciences Naturelles 28, Avenue Valrose 06108 Nice cedex 2 France; Center for Integrative Genomics, University of Lausanne, Genopode, CH-1015 Lausanne, Switzerland

* To whom correspondence should be addressed. E-mail: vincent.laudet{at}enslyon.fr.

Recent evidence has emerged that PPAR{alpha}, which is largely involved in lipid metabolism, can play an important role in connecting circadian biology and metabolism. In the present study, we investigated the mechanisms by which PPAR{alpha} influences the pacemakers acting in the central clock located in the suprachiasmatic nucleus and in the peripheral oscillator of the liver. We demonstrate that PPAR{alpha} plays a specific role in the peripheral circadian control as it is required to maintain the circadian rhythm of the master clock gene bmal1 in vivo. This regulation occurs via a direct binding of PPAR{alpha} on a PPRE located in the bmal1 promoter. Reversely, BMAL1 is an upstream regulator of PPAR{alpha} gene expression. We further demonstrate that fenofibrate induces circadian rhythm of clock gene expression in cell culture and up-regulates hepatic bmal1 in vivo. Altogether, these results provide evidence for an additional regulatory feedback loop involving BMAL1 and PPAR{alpha} in peripheral clocks.
Key words: PPAR{alpha} • BMAL1 • Peripheral clock • Fibrates

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Nuclear Receptors:   PPARα  |  REV-ERBα



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