IDOL G51S Variant Is Associated With High Blood Cholesterol and Increases Low-Density Lipoprotein Receptor Degradation
| Autor: | Yi-Tong Ma, Yan Wang, Jin-Kai Wang, Zhen-Yan Fu, Yu-Xia Zhou, Jian Wei, Dilare Adi, Ao Hu, Jie Luo, Ya-Jie Meng, Gulinaer Baituola, Xiao-Yi Lu, Bao-Liang Song, Xiang-Feng Lu |
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| Rok vydání: | 2019 |
| Předmět: |
Adult
Male Hyperlipoproteinemias medicine.medical_specialty Ubiquitin-Protein Ligases Low-density lipoprotein receptor degradation Mice chemistry.chemical_compound Ubiquitin Internal medicine medicine Animals Humans Risk factor Cells Cultured Mice Inbred BALB C Whole Genome Sequencing biology Chemistry Cholesterol Heterozygote advantage Cholesterol LDL Middle Aged Ubiquitin ligase Disease Models Animal Endocrinology Gene Expression Regulation Receptors LDL LDL receptor Blood cholesterol biology.protein RNA Female lipids (amino acids peptides and proteins) Cardiology and Cardiovascular Medicine |
| Zdroj: | Arteriosclerosis, Thrombosis, and Vascular Biology. 39:2468-2479 |
| ISSN: | 1524-4636 1079-5642 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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