IDOL G51S Variant Is Associated With High Blood Cholesterol and Increases Low-Density Lipoprotein Receptor Degradation

作者：Dilare Adi, Xiao-Yi Lu, Zhen-Yan Fu, Zhen-Yan Fu, Jian Wei, Gulinaer Baituola, Ya-Jie Meng, Yu-Xia Zhou, Ao Hu, Jin-Kai Wang, Xiang-Feng Lu, Xiang-Feng Lu, Yan Wang, Bao‐Liang Song, Yi-Tong Ma, Jie Luo · 发表于：Arteriosclerosis Thrombosis and Vascular Biology · 年份：2019 · DOI：10.1161/atvbaha.119.312589 · 被引用次数：24 · 研究领域：Diabetes, Cardiovascular Risks, and Lipoproteins、Peroxisome Proliferator-Activated Receptors、Nuclear Structure and Function

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.