Experimental & molecular medicineAug 24, 2012

Daily rhythm control of LDL receptor gene activity by CLOCK/BMAL1 and Hes proteins

Circadian Biology Weekly Brief ↗PubMed ↗DOI ↗

Updated Apr 4, 2026

Abstract

LDLR mRNA oscillates in the liver in a functional clock-dependent manner.

Blood glucose, plasma triglyceride, and cholesterol levels vary distinctly throughout the day in mice.
Three potential E-box sequences identified in the human LDLR promoter suggest regulation by specific transcription factors.
The CLOCK/BMAL1 complex is associated with the upregulation of LDLR promoter activity regardless of serum levels.
Hes1 and Hes6 can downregulate LDLR expression, but this effect is only observed in serum-depleted conditions.
Hes6 and Hes1 mRNA levels oscillate in an anti-phasic manner in wild-type mice but not in per1-/-per2-/- mice.
Conservation of three E-boxes among mouse, rat, and human hes6 genes indicates a similar regulatory mechanism across species.

Simplified

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 Hes6 expression were analyzed. It was found that positive circadian transcription factor complex CLOCK/BMAL1 upregulated human LDLR promoter activity in a serum-independent manner, while Hes family members Hes1 and 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/BMAL1 and Hes family members Hes1 and Hes6.

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Daily rhythm control of LDL receptor gene activity by CLOCK/BMAL1 and Hes proteins

Abstract

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