IDOL, inducible degrader of low-density lipoprotein receptor, serves as a potential therapeutic target for dyslipidemia

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• 作者：Cai-ping Zhang^a ; ^c ; ¹ ; Ying Tian^c ; ¹ ; Min Zhang^c ; Qin-hui Tuo^b ; Jian-xiong Chen^b ; ^d ; Duan-fang Liao^b ; ^{dfliao66@aliyun.com" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Non-HDL-C ; non-high density lipoprotein cholesterol ; LDL-C ; low-density lipoprotein cholesterol ; ASCVD ; atherosclerotic cardiovascular disease ; HMGCR ; 3-hydroxy-3-methylglutaryl-coenzyme A reductase ; SREBPs ; sterol response element binding proteins ; PCSK9 ; pro-protein convertase subtilisin/kexin type 9 ; IDOL ; inducible degrader of LDLR ; LXRs ; liver X receptors ; MYLIP ; myosin regulatory light chain interacting protein ; FERM ; frame of ezrin/radixin/moesin homology ; RING ; really interesting new gen
• 刊名：Medical Hypotheses
• 出版年：2016
• 出版时间：January 2016
• 年：2016
• 卷：86
• 期：Complete
• 页码：138-142
• 全文大小：415 K

文摘

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.