PPARα (peroxisome-proliferator-activated receptor α) is a member of the nuclear receptor superfamily of ligand-activated transcription factors that regulate the expression of genes associated with lipid metabolism. In the present study, we show that circadian expression of mouse PPARα mRNA requires the basic helix–loop–helix PAS (Per-Arnt-Sim) protein CLOCK, a core component of the negative-feedback loop that drives circadian oscillators in mammals. The circadian expression of PPARα mRNA was abolished in the liver of homozygous Clock mutant mice. Using wild-type and Clock-deficient fibroblasts derived from homozygous Clock mutant mice, we showed that the circadian expression of PPARα mRNA is regulated by the peripheral oscillators in a CLOCK-dependent manner. Transient transfection and EMSAs (electrophoretic mobility-shift assays) revealed that the CLOCK–BMAL1 (brain and muscle Arnt-like protein 1) heterodimer transactivates the PPARα gene via an E-box-rich region located in the second intron. This region contained two perfect E-boxes and four E-box-like motifs within 90 bases. ChIP (chromatin immunoprecipitation) also showed that CLOCK associates with this E-box-rich region in vivo. Circadian expression of PPARα mRNA was intact in the liver of insulin-dependent diabetic and of adrenalectomized mice, suggesting that endogenous insulin and glucocorticoids are not essential for the rhythmic expression of the PPARα gene. These results suggested that CLOCK plays an important role in lipid homoeostasis by regulating the transcription of a key protein, PPARα.
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Research Article|
March 08 2005
CLOCK is involved in the circadian transactivation of peroxisome-proliferator-activated receptor α (PPARα) in mice
Katsutaka OISHI;
Katsutaka OISHI
*Clock Cell Biology Research Group, Institute for Biological Resources and Functions, National Institute of Advanced Industrial Science and Technology, Central 6, 1-1-1 Higashi, Tsukuba, Ibaraki 305-8566, Japan
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Hidenori SHIRAI;
Hidenori SHIRAI
*Clock Cell Biology Research Group, Institute for Biological Resources and Functions, National Institute of Advanced Industrial Science and Technology, Central 6, 1-1-1 Higashi, Tsukuba, Ibaraki 305-8566, Japan
†Institute of Applied Biochemistry, University of Tsukuba, Tsukuba, Ibaraki 305-8502, Japan
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Norio ISHIDA
Norio ISHIDA
1
*Clock Cell Biology Research Group, Institute for Biological Resources and Functions, National Institute of Advanced Industrial Science and Technology, Central 6, 1-1-1 Higashi, Tsukuba, Ibaraki 305-8566, Japan
†Institute of Applied Biochemistry, University of Tsukuba, Tsukuba, Ibaraki 305-8502, Japan
1To whom correspondence should be addressed (email n.ishida@aist.go.jp).
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Publisher: Portland Press Ltd
Received:
July 06 2004
Revision Received:
October 15 2004
Accepted:
October 25 2004
Accepted Manuscript online:
October 25 2004
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London
2005
Biochem J (2005) 386 (3): 575–581.
Article history
Received:
July 06 2004
Revision Received:
October 15 2004
Accepted:
October 25 2004
Accepted Manuscript online:
October 25 2004
Citation
Katsutaka OISHI, Hidenori SHIRAI, Norio ISHIDA; CLOCK is involved in the circadian transactivation of peroxisome-proliferator-activated receptor α (PPARα) in mice. Biochem J 15 March 2005; 386 (3): 575–581. doi: https://doi.org/10.1042/BJ20041150
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