Cholesterol diet enhances daily rhythm of Pai-1 mRNA in the mouse liver

• Published in: American journal of physiology: endocrinology and metabolism 2004-10, Vol.287 (4), p.E644-E651
• Main Authors: Kudo, Takashi, Nakayama, Emiko, Suzuki, Sawako, Akiyama, Masashi, Shibata, Shigenobu
• Format: Article
• Language: English
• Subjects: Animals; ARNTL Transcription Factors; Basic Helix-Loop-Helix Transcription Factors; Caloric Restriction; Cholesterol - blood; Cholesterol - metabolism; Cholesterol, Dietary - pharmacology; Circadian Rhythm - physiology; DNA Primers; DNA-Binding Proteins - physiology; Gene Expression Regulation - drug effects; Liver - drug effects; Liver - metabolism; Male; Mice; Mice, Inbred ICR; Myocardium - metabolism; Nuclear Receptor Subfamily 4, Group A, Member 1; Plasminogen Activator Inhibitor 1 - biosynthesis; Plasminogen Activator Inhibitor 1 - genetics; Receptors, Cytoplasmic and Nuclear; Receptors, LDL - biosynthesis; Receptors, LDL - genetics; Receptors, Steroid; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - biosynthesis; RNA, Messenger - genetics; Second Messenger Systems - drug effects; Second Messenger Systems - physiology; Signal Transduction - drug effects; Signal Transduction - physiology; Suprachiasmatic Nucleus - physiology; Transcription Factors - biosynthesis; Transcription Factors - genetics; Transcription Factors - physiology; Tumor Necrosis Factor-alpha - physiology
• ISSN: 0193-1849; 1522-1555
• DOI: 10.1152/ajpendo.00095.2004

Department of Pharmacology, School of Science and Engineering, Waseda University, Tokyo 202-0021, Japan Submitted 26 February 2004 ; accepted in final form 2 June 2004 Myocardial infarction frequently occurs in the morning, a phenomenon in part resulting from the downregulation of fibrinolytic activity. Plasminogen activator inhibitor-1 (PAI-1) is a key factor behind fibrinolytic activity, and its gene expression is controlled under the circadian clock gene in the mouse heart and liver. Hypercholesterolemia has been associated with impaired fibrinolysis due to enhanced PAI-1 activity, which has also been implicated in atherosclerosis. The aim of this study was to decipher whether the Pai-1 gene is still expressed daily with hypercholesterolemia. Hypercholesterolemia (1% cholesterol diet) did not significantly affect the daily expression of clock genes ( Per2 and Bmal1 ) and clock-controlled genes ( Dbp and E4bp4 ) in the liver ( P > 0.05); however, daily expression of the Pai-1 gene and Pai-1 promoter regulating factor genes such as Nr4a1 was significantly upregulated ( P < 0.01). Daily restricted feeding for 4 h during the day reset the gene expression of Per2 , Pai-1 , Nr4a1 , and Tnf- . Lesion of the suprachiasmatic nucleus, the location of the main clock system, led to loss of Per2 and Pai-1 daily expression profiles. In the present experiments, we demonstrated that hypercholesterolemia enhanced daily expression of the Pai-1 , Tnf- , and Nr4a1 genes in the mouse liver without affecting clock and clock-controlled genes. Therefore, the risk or high frequency of acute atherothrombotic events in the morning still seems to be a factor that may be augmented under conditions of hypercholesterolemia. circadian; clock gene; hypercholesterolemia; suprachiasmatic; fibrinolytic Address for reprint requests and other correspondence: S. Shibata, Dept. of Pharmacology, School of Science and Engineering, Waseda Univ., Higashifushimi 2-7-5, Nishitokyo-Shi, Tokyo 202-0021, Japan (E-mail: shibatas{at}waseda.jp )