CLOCK/BMAL1 is Involved in Lipid Metabolism via Transactivation of the Peroxisome Proliferator-activated Receptor (PPAR) Response Element

  • Inoue Ikuo
    Fourth Department of Medicine, Research Center for Genomic Medicine, Saitama Medical School, Saitama, Japan.
  • Shinoda Yuichi
    Department of Biochemistry, Research Center for Genomic Medicine, Saitama Medical School, Saitama, Japan.
  • Ikeda Masaaki
    Department of Physiology, Research Center for Genomic Medicine, Saitama Medical School, Saitama, Japan. Molecular Clock Project, Research Center for Genomic Medicine, Saitama Medical School, Saitama, Japan.
  • Hayashi Kenji
    Fourth Department of Medicine, Research Center for Genomic Medicine, Saitama Medical School, Saitama, Japan.
  • Kanazawa Kenta
    Fourth Department of Medicine, Research Center for Genomic Medicine, Saitama Medical School, Saitama, Japan.
  • Nomura Masahiko
    Department of Physiology, Research Center for Genomic Medicine, Saitama Medical School, Saitama, Japan.
  • Matsunaga Toshiyuki
    Department of Biochemistry, Research Center for Genomic Medicine, Saitama Medical School, Saitama, Japan.
  • Xu Haiyuan
    Fourth Department of Medicine, Research Center for Genomic Medicine, Saitama Medical School, Saitama, Japan. Department of Physiology, Research Center for Genomic Medicine, Saitama Medical School, Saitama, Japan. Molecular Clock Project, Research Center for Genomic Medicine, Saitama Medical School, Saitama, Japan.
  • Kawai Shinichiro
    Department of Biochemistry, Research Center for Genomic Medicine, Saitama Medical School, Saitama, Japan.
  • Awata Takuya
    Fourth Department of Medicine, Research Center for Genomic Medicine, Saitama Medical School, Saitama, Japan.
  • Komoda Tsugikazu
    Department of Biochemistry, Research Center for Genomic Medicine, Saitama Medical School, Saitama, Japan.
  • Katayama Shigehiro
    Fourth Department of Medicine, Research Center for Genomic Medicine, Saitama Medical School, Saitama, Japan.

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Lipid absorption and metabolism are regulated by feeding and by the circadian system. It has been suggested that the expression of enzymes involved in lipid metabolism is directly controlled by the clock system. This study was designed to examine whether or not the CLOCK/BMAL1 heterodimer has transcriptional activity for genes via the peroxisome proliferator-activated receptor response element (PPRE). Male mice 8-12 weeks old were maintained under a 12:12 hour light-dark cycle for at least two weeks before the day of the experiment. The mRNA profiles of BMAL1 and of the PPAR target genes acyl-CoA oxidase (AOX), 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) synthase and cellular retinol binding protein II</B> (CRBPII</B>) were measured in intestine. The direct effects of CLOCK/BMAL1 on the promoter activities of those three enzymes were assessed in vitro by luciferase assay. The expression of PPAR target genes changed in a cyclical manner that followed expression of BMAL1. The promoter activities of the three enzymes were increased by CLOCK/BMAL1 expression. After deletion of the PPRE from the CRBPII</B> construct, CLOCK/BMAL1 did not affect transactivation. CLOCK/BMAL1 transactivates PPAR target genes via the PPRE.

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