Proxisome proliferator-activated receptor-α mediates high-fat, diet-enhanced daily oscillation of plasminogen activator inhibitor-1 activity in mice.
Acute thrombotic events frequently occur in the early morning among hyperlipidemic patients. The activity of plasminogen activator inhibitor-1 (PAI-1), a potent inhibitor of the fibrinolytic system, oscillates daily, and this is considered one mechanism that underlies the morning onset of acute thrombotic events in hyperlipidemia. Although several studies have reported the expression of the PAI-1 gene is under the control of the circadian clock system, the molecular mechanism of the circadian transactivation of PAI-1 gene under hyperlipidemic conditions remains to be elucidated. Here, the authors investigated whether hyperlipidemia induced by a high-fat diet (HFD) enhances the daily oscillation of plasma PAI-1 activity in mice. The mRNA levels of the PAI-1 gene were increased and rhythmically fluctuated with high-oscillation amplitude in the livers of wild-type mice fed with the HFD. Circadian expression of proxisome proliferator-activated receptor-α (PPARα) mRNA was also augmented as well as that of PAI-1. Chromatin immunoprecipitation showed the HFD-induced hyperlipidemia significantly increased the binding of PPARα to the PAI-1 promoter. Luciferase reporter analysis using primary hepatocytes revealed CLOCK/BMAL1-mediated PAI-1 promoter activity was synergistically enhanced by cotransfection with PPARα/retinoid X receptor-α (RXRα), and this synergistic transactivation was repressed by negative limbs of the circadian clock, PERIOD2 and CRYPTOCHROME1. As expected, HFD-induced PAI-1 mRNA expression was significantly attenuated in PPARα-null mice. These results suggest a molecular link between the circadian clock and lipid metabolism system in the regulation of PAI-1 gene expression, and provide an aid for understanding why hyperlipidemia increases the risk of acute thrombotic events in the morning.
Department of Biochemistry, Faculty of Pharmaceutical Sciences, Fukuoka University, 8-19-1 Nanakuma Jonan-ku, Fukuoka, Japan.
Satoru
S
Hayashida
Yukako
Y
Kuramoto
Satoru
S
Koyanagi
Katsutaka
K
Oishi
Junya
J
Fujiki
Naoya
N
Matsunaga
Eriko
E
Ikeda
Shigehiro
S
Ohdo
Hiroshi
H
Shimeno
Shinji
S
Soeda
D056930:ARNTL Transcription Factors / Q000235:genetics; D000273:Adipose Tissue / Q000502:physiology; D000818:Animals; D002784:Cholesterol / Q000097:blood; D002843:Chromatin / Q000502:physiology; D002940:Circadian Rhythm; D056931:Cryptochromes / Q000235:genetics; D004032:Diet; D005230:Fatty Acids, Nonesterified / Q000097:blood; D017930:Genes, Reporter; D006321:Heart / Q000502:physiology; D006801:Humans; D007668:Kidney / Q000502:physiology; D008099:Liver / Q000502:physiology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009991:Oscillometry; D047493:PPAR alpha / Q000235:genetics / Q000502:physiology*; D056950:Period Circadian Proteins / Q000235:genetics; D017395:Plasminogen Activator Inhibitor 1 / Q000097:blood* / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013927:Thrombosis / Q000453:epidemiology; D014158:Transcription, Genetic; D014280:Triglycerides / Q000097:blood
D056930:ARNTL Transcription Factors; C538961:Bmal1 protein, mouse; D002843:Chromatin; C538964:Cry1 protein, mouse; D056931:Cryptochromes; D005230:Fatty Acids, Nonesterified; D047493:PPAR alpha; C513312:Per2 protein, mouse; D056950:Period Circadian Proteins; D017395:Plasminogen Activator Inhibitor 1; D014280:Triglycerides; D002784:Cholesterol