Zhang Cai-ping, Tian Ying, Zhang Min, Tuo Qin-hui, Chen Jian-xiong, Liao Duan-fang
Medical College, University of South China, 28# W Changsheng Rd, Hengyang 421001, Hunan, China; Department of Biochemistry and Molecular Biology, University of South China, 28# W Changsheng Rd, Hengyang 421001, Hunan, China.
Department of Biochemistry and Molecular Biology, University of South China, 28# W Changsheng Rd, Hengyang 421001, Hunan, China.
Med Hypotheses. 2016 Jan;86:138-42. doi: 10.1016/j.mehy.2015.11.010. Epub 2015 Nov 14.
Low-density lipoprotein cholesterol (LDL-C) is the hall marker for the atherosclerotic cardiovascular disease (ASCVD). It has been shown that over 70% of circulating LDL-C is metabolized through binding and activation of hepatic LDL receptor (LDLR). Genetic LDLR mutations cause hypercholesterolemia in the patients. Therefore, elevation of LDLR levels is beneficial for the treatment of dyslipidemia. LDLR expression is regulated by the SREBP2/PCSK9 pathways. Targeting SREBP2/PCSK9 pathways by statins and human monoclonal PCSK9 antibody has been shown to reduce the progression of ASVCD. Recent studies identified that inducible degrader of LDLR (IDOL) is a novel regulator of LDLR. IDOL is an E3-ubiquitin ligase regulated via liver X receptors (LXRs) binding to the upstream of translation start site of IDOL. IDOL modulates LDLR distribution through ubiquitination and degradation of LDLR in lysosomes. Genome-wide association studies (GWAS) have revealed that the nonsynonymous substitution rs9370867 of IDOL probably contributes to the variability of circulating LDL levels. Recently studies also demonstrated that IDOL influences PCSK9 expression in a LDLR/SREBP2-dependent manner. Based upon these novel findings, we hypothesize that IDOL and PCSK9 would have a synergistic effect on LDLR distribution. Specifically, loss of IDOL increases LDLR distribution in the hepatic cell, and subsequently reduces serum LDL-C levels in dyslipidemic patients. IDOL might be a potential therapeutic target for the treatment of ASCVD.
低密度脂蛋白胆固醇（LDL-C）是动脉粥样硬化性心血管疾病（ASCVD）的标志性指标。研究表明，超过70%的循环LDL-C通过肝脏LDL受体（LDLR）的结合和激活进行代谢。LDLR基因的突变会导致患者出现高胆固醇血症。因此，提高LDLR水平有利于血脂异常的治疗。LDLR的表达受SREBP2/PCSK9通路调控。他汀类药物和人源单克隆PCSK9抗体作用于SREBP2/PCSK9通路已被证明可减缓ASVCD的进展。最近的研究发现，LDLR诱导降解物（IDOL）是LDLR的一种新型调节因子。IDOL是一种E3泛素连接酶，通过肝脏X受体（LXR）与IDOL翻译起始位点上游结合进行调控。IDOL通过对LDLR进行泛素化修饰并使其在溶酶体中降解来调节LDLR的分布。全基因组关联研究（GWAS）显示，IDOL的非同义替换rs9370867可能与循环LDL水平的变异性有关。最近的研究还表明，IDOL以LDLR/SREBP2依赖的方式影响PCSK9的表达。基于这些新发现，我们推测IDOL和PCSK9在LDLR分布上可能具有协同作用。具体而言，IDOL缺失会增加肝细胞中LDLR的分布，进而降低血脂异常患者的血清LDL-C水平。IDOL可能是治疗ASCVD的一个潜在治疗靶点。
