PROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-α MEDIATES HIGH-FAT, DIET-ENHANCED DAILY OSCILLATION OF PLASMINOGEN ACTIVATOR INHIBITOR-1 ACTIVITY IN MICE

Abstract

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.

Systematic analysis of circadian genes using genome-wide cDNA microarrays in the inflammatory bowel disease transcriptome

“…ARNTL2 may functionally replace ARNTL, and PER2 preferentially inhibits ARNTL2:CLOCK heterodimer activity, emphasizing its negative role and a positive role of ARNTL2 in the circadian transcription (Sasaki et 2010). ARNTL:CLOCK and ARNTL2:CLOCK heterodimers powerfully activate the promoter of the gene coding for Plasminogen Activator Inhibitor (PAI)-1, officially called SERPINE1 and located on the seventh chromosome (7q21.3-q22), underlying the circadian variation in circulating PAI-1 (Hayashida et al, 2010;Maemura et al, 2000;Oishi, 2009;Oishi et al, 2009). ARNTL2:CLOCK, binding two E-box enhancers in the promoter, is twice more potent than ARNTL:CLOCK in its ability to activate SERPINE1 (Schoenhard et al, 2003), and in CD patients we have found up-regulation of the gene encoding PAI-1.…”

ARNTL2 and SERPINE1: potential biomarkers for tumor aggressiveness in colorectal cancer

“…In addition, high preoperative plasma concentrations of PAI-1 are associated with shorter survival in patients with colorectal cancer (Nielsen et al 1998). Both CLOCK:ARNTL and CLOCK:ARNTL2 heterodimers powerfully activate the promoter of the PAI-1 gene, officially called SERPINE1 and located on the seventh chromosome (7q21.3-q22), underlying the circadian variation in circulating PAI-1 (Angleton et al 1989;Kurnik 1995;Maemura et al 2000;Oishi et al 2009;Oishi 2009;Hayashida et al 2010). CLOCK:ARNTL2, binding two E-box enhancers in the promoter, is much more potent than CLOCK:ARNTL in its ability to activate SERPINE1 (Schoenhard et al 2003;Sasaki et al 2009).…”

Circadian rhythms and clocks in adipose tissues: current insights

“…119,120 In murine WAT, mRNA expression of resistin and visfatin peaks during the dark phase, 16,120,122 while mRNA expression of PAI-1 is highest during the light phase. 114 Activity of plasma PAI-1, however, is highest at the beginning of the active phase. 114,123,124 TNFα peaks in serum of lean rats during the inactive phase.…”

“…114 Activity of plasma PAI-1, however, is highest at the beginning of the active phase. 114,123,124 TNFα peaks in serum of lean rats during the inactive phase. 125,126 Interestingly, if mice are fed a HFD, the peak of serum TNFα shifts to the active phase.…”

“…Expression of PAI-1 and visfatin is known to be directly controlled by the circadian clock. [114][115][116][117][118][119][120][121] Additionally, visfatin can feed back on the circadian clock via the NAD+ salvage pathway. 119,120 In murine WAT, mRNA expression of resistin and visfatin peaks during the dark phase, 16,120,122 while mRNA expression of PAI-1 is highest during the light phase.…”