Circadian regulation of low density lipoprotein receptor promoter activity by CLOCK/BMAL1, Hes1 and Hes6
Open accessAbstract
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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HES6 encodes a protein that contributes to circadian regulation of LDLR and cholesterol homeostasis.
“HES6 encodes a protein that contributes to circadian regulation of LDLR and cholesterol homeostasis (Lee et al. 2012).”
From Archaic Introgression Shaped Human Circadian Traits (2023) · cites this paper as Lee et al. 2012
The Abstract and Discussion report that Hes6 regulates LDLR promoter activity and is involved in its circadian control. The Discussion says Hes6 *may* have a role in cholesterol homeostasis; it does not establish that contribution as a fact. (LLM, conf=0.84)
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References 38 · Cited by 43
- Authors
- Lee, Y.-J., Han, D.-H., Pak, Y. K., & Cho, S.
- Affiliations
- Kyung Hee University (KR)
- Corresponding author
- Cho, Sehyung
- ORCID
- Pak, Youngmi Kim
- Venue
- Experimental & Molecular Medicine
- Published
- 2012
- Volume
- 44
- Issue
- 11
- Pages
- 642
- ISSN
- 1226-3613 (ISSN-L)
- 2092-6413
- PMC
- PMC3509181
- OpenAlex
- W2053488916
- Cited by
- 43
- References
- 38
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 2 · 2023: 7 · 2022: 4 · 2021: 7 · 2020: 1 · 2019: 4 · 2017: 3 · 2016: 2 · 2015: 2 · 2014: 6 · 2013: 1
- FWCI
- 1.28
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by-nc
- Locations
- Experimental & Molecular Medicine (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Funders
- Kyung Hee University
- Ewha Womans University
- Korea University
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Keywords
- LDL receptor, circadian rhythm, Clock/BMAL1, Hes1, HES6, E-box, sterol regulatory element, cholesterol homeostasis, hepatic gene expression, clock genes
- MeSH terms
- Transcription Factor HES-1, Animals, Base Sequence, Cholesterol, Circadian Rhythm, Exons, Gene Expression Regulation, Homeostasis, Humans, Liver, Male, Mice, Inbred C57BL, Promoter Regions, Genetic, Receptors, LDL, Repressor Proteins, Transcription, Genetic, Homeodomain Proteins, E-Box Elements, Mice, Basic Helix-Loop-Helix Transcription Factors, Basic Helix-Loop-Helix Proteins, CLOCK Proteins, ARNTL Transcription Factors, Hep G2 Cells
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