Reciprocal regulation of brain and muscle Arnt-like protein 1 and peroxisome proliferator-activated receptor alpha defines a novel positive feedback loop in the rodent liver circadian clock.
Recent evidence has emerged that peroxisome proliferator-activated receptor alpha (PPARalpha), 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 PPARalpha influences the pacemakers acting in the central clock located in the suprachiasmatic nucleus and in the peripheral oscillator of the liver. We demonstrate that PPARalpha plays a specific role in the peripheral circadian control because it is required to maintain the circadian rhythm of the master clock gene brain and muscle Arnt-like protein 1 (bmal1) in vivo. This regulation occurs via a direct binding of PPARalpha on a potential PPARalpha response element located in the bmal1 promoter. Reversely, BMAL1 is an upstream regulator of PPARalpha gene expression. We further demonstrate that fenofibrate induces circadian rhythm of clock gene expression in cell culture and up-regulates hepatic bmal1 in vivo. Together, these results provide evidence for an additional regulatory feedback loop involving BMAL1 and PPARalpha in peripheral clocks.
Structure and Evolution of Nuclear Receptors, Centre National de la Recherche Scientifique (CNRS) Unité Mixte de Recherche 5161, Institut Fédératif de Recherche (IFR) 128 BioSciences Lyon-Gerland, Lyon, France.
Laurence
L
Canaple
Juliette
J
Rambaud
Ouria
O
Dkhissi-Benyahya
Béatrice
B
Rayet
Nguan Soon
NS
Tan
Liliane
L
Michalik
Franck
F
Delaunay
Walter
W
Wahli
Vincent
V
Laudet
D056930:ARNTL Transcription Factors; D000818:Animals; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000378:metabolism*; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D056926:CLOCK Proteins; D002478:Cells, Cultured; D002940:Circadian Rhythm; D015536:Down-Regulation; D004435:Eating / Q000502:physiology; D025461:Feedback, Physiological; D005260:Female; D005786:Gene Expression Regulation; D008099:Liver / Q000502:physiology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity; D009132:Muscles / Q000378:metabolism*; D047493:PPAR alpha / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D013493:Suprachiasmatic Nucleus / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics
D056930:ARNTL Transcription Factors; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D051792:Basic Helix-Loop-Helix Proteins; D056926:CLOCK Proteins; D047493:PPAR alpha; D012333:RNA, Messenger; D015534:Trans-Activators; C538961:Bmal1 protein, mouse; C538944:Clock protein, mouse; C538945:Clock protein, rat