IDOL G51S Variant Is Associated With High Blood Cholesterol and Increases Low-Density Lipoprotein Receptor Degradation
IDOL G51S Variant Is Associated With High Blood Cholesterol and Increases Low-Density Lipoprotein Receptor Degradation
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IDOL G51S 变体与高血液胆固醇相关并增加低密度脂蛋白受体降解
DOI：
10.1161/atvbaha.119.312589
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发表时间：
2019-12-01
影响因子：
8.7
通讯作者：
Luo, Jie
中科院分区：
文献类型：
--
作者：
Adi, Dilare;Lu, Xiao-Yi;Luo, Jie
目的：低密度脂蛋白胆固醇(LDL-C)水平升高是心血管疾病的主要危险因素。E3泛素连接酶(IDOL)通过泛素化LDLR的C-末端尾部，介导LDLR的降解。但Idol在小鼠和人的肝脏中的表达谱有很大不同。美国偶像是否能够调节人类体内的低密度脂蛋白-C水平仍有待确定。方法和结果：通过全外显子测序，我们在一个中国维吾尔族家庭中发现了一个非同义突变rs149696224，该突变导致了一个中国维吾尔族家庭的G51S(氨基酸51位甘氨酸到丝氨酸的替换)。大队列分析显示，Idol G51S携带者(+/G51S)的低密度脂蛋白-C水平显著升高。从机制上讲，G51S突变通过抑制Idol蛋白的二聚化和防止自身泛素化和随后的蛋白酶体降解来稳定Idol蛋白。IDOL(G51S)具有更强的促进LDLR泛素化和降解的能力。腺相关病毒介导的Idol(G51S)在小鼠肝脏中的表达降低了肝脏的低密度脂蛋白受体，并提高了血清低密度脂蛋白-C、总胆固醇和甘油三酯的水平。结论：我们的研究表明，Idol(G51S)是导致人类和小鼠高低密度脂蛋白-C的功能获得变异体。这些结果表明，美国偶像是调节人类胆固醇水平的关键因素。
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.