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.

Effects of statins on the inducible degrader of low-density lipoprotein receptor in familial hypercholesterolemia

“…Studies in non-human primates show that gain or loss of IDOL function leads to a corresponding increase and reduction in plasma LDL levels, respectively ( 4 ). In addition to experimental data, genetic studies have provided further evidence to support the notion that IDOL may potentially be involved in LDL metabolism ( 5 , 6 , 7 ). A recent study in children with untreated familial hypercholesterolemia (FH) has shown that plasma concentration of IDOL was elevated and was significantly associated with total and LDL cholesterol levels ( 8 ).…”

Genetic polymorphism of IDOL gene was associated with the susceptibility of coronary artery disease in Han population in Xinjiang, China

“…The relationship between plasma lipid profiles and the IDOL gene polymorphisms was poor, and previous studies showed inconsistent results. Adi et al [ 24 ] reported that the rs149696224 SNP in the IDOL gene was related to the high LDL-C levels in the Chinese Uygur population. Their study showed the G51S mutation stabilizes IDOL protein through inhibiting its dimerization and self-ubiquitination and, consequently, leading to increased LDLR degradation.…”

Integrative genomic expression analysis reveals stable differences between lung cancer and systemic sclerosis

“…Myosin regulatory light chain interacting protein (MYLIP, also named IDOL) is an important ubiquitin E3 ligase, which mediates low density lipoprotein receptor (LDLR) degradation through ubiquitination reaction and affect blood lipid levels [50]. Previous reports indicated the LDLR-related protein (LRP1B) was discovered as a putative tumor suppressor and frequently inactivated in lung cancer cells [51,52].…”