CLOCK/BMAL1 is involved in lipid metabolism via transactivation of the peroxisome proliferator-activated receptor (PPAR) response element.
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 (CRBPII) 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 construct, CLOCK/BMAL1 did not affect transactivation. CLOCK/BMAL1 transactivates PPAR target genes via the PPRE.
Inoue
Ikuo
I
Fourth Department of Medicine, Research Center for Genomic Medicine, Saitama Medical School, Saitama, Japan. i1901018@saitama-med.ac.jp
Shinoda
Yuichi
Y
Ikeda
Masaaki
M
Hayashi
Kenji
K
Kanazawa
Kenta
K
Nomura
Masahiko
M
Matsunaga
Toshiyuki
T
Xu
Haiyuan
H
Kawai
Shinichiro
S
Awata
Takuya
T
Komoda
Tsugikazu
T
Katayama
Shigehiro
S
D056930:ARNTL Transcription Factors; D042962:Acyl-CoA Oxidase / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D056926:CLOCK Proteins; D002940:Circadian Rhythm / Q000502:physiology; D006904:Hydroxymethylglutaryl-CoA Synthase / Q000235:genetics / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism; D050356:Lipid Metabolism; D008297:Male; D051379:Mice; D047492:Peroxisome Proliferator-Activated Receptors / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D012177:Retinol-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D054840:Retinol-Binding Proteins, Cellular; D015534:Trans-Activators / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology*
D056930:ARNTL Transcription Factors; D042962:Acyl-CoA Oxidase; D051792:Basic Helix-Loop-Helix Proteins; D056926:CLOCK Proteins; D006904:Hydroxymethylglutaryl-CoA Synthase; D047492:Peroxisome Proliferator-Activated Receptors; D012333:RNA, Messenger; D012177:Retinol-Binding Proteins; D054840:Retinol-Binding Proteins, Cellular; D015534:Trans-Activators; D014157:Transcription Factors; C538961:Bmal1 protein, mouse; C518460:Rbp2 protein, mouse; C538944:Clock protein, mouse