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IDOL G51S Variant Is Associated With High Blood Cholesterol and Increases Low-Density Lipoprotein Receptor Degradation
Abstract
Objective: A high level of LDL-C (low-density lipoprotein cholesterol) is a major risk factor for cardiovascular disease. The E3 ubiquitin ligase named IDOL (inducible degrader of the LDLR [LDL receptor]; also known as MYLIP [myosin regulatory light chain interacting protein]) mediates degradation of LDLR through ubiquitinating its C-terminal tail. But the expression profile of IDOL differs greatly in the livers of mice and humans. Whether IDOL is able to regulate LDL-C levels in humans remains to be determined. Approach and Results: By using whole-exome sequencing, we identified a nonsynonymous variant rs149696224 in the IDOL gene that causes a G51S (Gly-to-Ser substitution at the amino acid site 51) from a Chinese Uygur family. Large cohort analysis revealed IDOL G51S carriers (+/G51S) displayed significantly higher LDL-C levels. Mechanistically, the G51S mutation stabilized IDOL protein by inhibiting its dimerization and preventing self-ubiquitination and subsequent proteasomal degradation. IDOL(G51S) exhibited a stronger ability to promote ubiquitination and degradation of LDLR. Adeno-associated virus-mediated expression of IDOL(G51S) in mouse liver decreased hepatic LDLR and increased serum levels of LDL-C, total cholesterol, and triglyceride. Conclusions: Our study demonstrates that IDOL(G51S) is a gain-of-function variant responsible for high LDL-C in both humans and mice. These results suggest that IDOL is a key player regulating cholesterol level in humans.
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The G51S mutation of IDOL increases IDOL protein stability and promotes IDOL-stimulated LDLR degradation.
“In support of this statement, the G51S mutation of IDOL increases IDOL protein stability and promotes IDOL-stimulated LDLR degradation (13).”
From SUMOylation of the ubiquitin ligase IDOL decreases LDL receptor levels and is reversed by SENP1 (2021) · cites this paper as [13]
IDOL stabilization modulates LDLR expression and blood LDL-C levels.
“These results highlight the importance of IDOL stabilization in modulating LDLR expression and blood LDL-C levels.”
From SUMOylation of the ubiquitin ligase IDOL decreases LDL receptor levels and is reversed by SENP1 (2021) · cites this paper as [13]
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Metadata
- Authors
- Adi, D., Lu, X.-Y., Fu, Z.-Y., Wei, J., Baituola, G., Meng, Y.-J., Zhou, Y.-X., Hu, A., Wang, J.-K., Lu, X.-F., Wang, Y., Song, B.-L., Ma, Y.-T., & Luo, J.
- Affiliations
- First Affiliated Hospital of Xinjiang Medical University (CN)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Wuhan University (CN)
- The People’s Hospital Nanchuan, Chongqing, China (Y.-J.M.)
- Corresponding author
- Adi, Dilare
- Lu, Xiao-Yi
- Fu, Zhen-Yan
- ORCID
- Venue
- Arteriosclerosis, Thrombosis, and Vascular Biology
- Published
- 2019-12
- Volume
- 39
- Issue
- 12
- Pages
- 2468-2479
- ISSN
- 1079-5642 (ISSN-L)
- 1524-4636
- OpenAlex
- W2979936870
- Semantic Scholar
- e63b281082ae59aafa036ea80d83df4b528870fc
- Cited by
- 24
- References
- 33
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 4 · 2023: 2 · 2022: 4 · 2021: 6 · 2020: 3 · 2019: 1
- FWCI
- 1.48
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Arteriosclerosis Thrombosis and Vascular Biology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Cholesterol and Lipid Metabolism
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipoproteins and Cardiovascular Health
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Keywords
- idols, LDL receptor degradation, LDL cholesterol, E3 ubiquitin ligase, gain-of-function mutations, protein stability, protein dimerization, self-ubiquitination, proteasomal degradation, hepatic cholesterol metabolism, familial hypercholesterolemia, cardiovascular risk
- MeSH terms
- Whole Genome Sequencing, Adult, Animals, Cells, Cultured, Disease Models, Animal, Female, Gene Expression Regulation, Humans, Hyperlipoproteinemias, Cholesterol, LDL, Male, Mice, Inbred BALB C, Middle Aged, Receptors, LDL, RNA, Ubiquitin-Protein Ligases, Mice
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