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논문 기본 정보
- 자료유형
- 학술저널
- 저자정보
- 발행연도
- 2012.1
- 수록면
- 642 - 652 (11page)
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Low density lipoprotein receptor (LDLR) plays an important role in the cholesterol homeostasis. We examined the possible circadian regulation of LDLR and mechanism(s) underlying it. In mice, blood glucose and plasma triglyceride, total and high density lipoprotein cholesterol varied distinctively throughout a day. In addition, LDLR mRNA oscillated in the liver in a functional clock-dependent manner. Accordingly,analysis of human LDLR promoter sequence revealed three putative E-boxes, raising the possible regulation of LDLR expression by E-box-binding transcription factors. To test this possibility, human LDLR promoter reporter constructs were transfected into HepG2 cells and the effects of CLOCK/BMAL1, Hes1, and Hes6expression were analyzed. It was found that positive circadian transcription factor complex CLOCK/BMAL1upregulated human LDLR promoter activity in a serumindependent manner, while Hes family members Hes1and Hes6 downregulated it only under serum-depleted conditions. Both effects were mapped to proximal promoter region of human LDLR, where mutation or deletion of well-known sterol regulatory element (SRE)abolished only the repressive effect of Hes1.
Interestingly, hes6 and hes1 mRNA oscillated in an anti-phasic manner in the wild-type but not in the per1-/-per2 -/- mouse. Comparative analysis of mouse,rat and human hes6 genes revealed that three E-boxes are conserved among three species. Transfection and site-directed mutagenesis studies with hes6 reporter constructs confirmed that the third E-box in the exon IV is functionally induced by CLOCK/BMAL1. Taken together, these results suggest that LDLR expression is under circadian control involving CLOCK/BMAL1and Hes family members Hes1 and Hes6.
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참고문헌 (26)
참고문헌 신청
Al Rayyes O / 1997 / Additive inhibitory effect of hydrocortisone and cyclosporine on low-density lipoprotein receptor activity in cultured HepG2 cells / Hepatology 26 : 967
Bae S / 2000 / The bHLH gene Hes6, an inhibitor of Hes1, promotes neuronal differentiation / Development 127 : 2933 ~ 2943
Balasubramaniam S / 1994 / Circadian rhythm in hepatic low-density-lipoprotein (LDL)-receptor expression and plasma LDL levels / Biochem J 298 : 39 ~ 43
Briggs MR / 1993 / Nuclear protein that binds sterol regulatory element of low density lipoprotein receptor promoter. I. Identification of the protein and delineation of its
Brown MS / 1986 / A receptor-mediated pathway for cholesterol homeostasis / Science 232 : 34 ~ 47
Bae S / 2000 / The bHLH gene Hes6, an inhibitor of Hes1, promotes neuronal differentiation / Development 127 : 2933 ~ 2943
Balasubramaniam S / 1994 / Circadian rhythm in hepatic low-density-lipoprotein (LDL)-receptor expression and plasma LDL levels / Biochem J 298 : 39 ~ 43
Briggs MR / 1993 / Nuclear protein that binds sterol regulatory element of low density lipoprotein receptor promoter. I. Identification of the protein and delineation of its
Brown MS / 1986 / A receptor-mediated pathway for cholesterol homeostasis / Science 232 : 34 ~ 47
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