title: IDOL, inducible degrader of low-density lipoprotein receptor, serves as a potential therapeutic target for dyslipidemia.
abstract: 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.
authors.affiliation: 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.
authors.forename: Cai-ping
authors.initials: CP
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry and Molecular Biology, University of South China, 28# W Changsheng Rd, Hengyang 421001, Hunan, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Tian
authors.affiliation: Department of Biochemistry and Molecular Biology, University of South China, 28# W Changsheng Rd, Hengyang 421001, Hunan, China.
authors.forename: Min
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Division of Stem Cell Regulation and Application, State Key Laboratory of Chinese Medicine Powder and Medicine Innovation in Hunan (incubation), Hunan University of Chinese Medicine, 300# Xueshi Rd, Hanpu Science & Education District, Changsha 410208, Hunan, China.
authors.forename: Qin-hui
authors.initials: QH
authors.lastname: Tuo
authors.affiliation: Division of Stem Cell Regulation and Application, State Key Laboratory of Chinese Medicine Powder and Medicine Innovation in Hunan (incubation), Hunan University of Chinese Medicine, 300# Xueshi Rd, Hanpu Science & Education District, Changsha 410208, Hunan, China; Dept Pharmacology & Toxicology, University of Mississippi Medical Center, USA.
authors.forename: Jian-xiong
authors.initials: JX
authors.lastname: Chen
authors.affiliation: Division of Stem Cell Regulation and Application, State Key Laboratory of Chinese Medicine Powder and Medicine Innovation in Hunan (incubation), Hunan University of Chinese Medicine, 300# Xueshi Rd, Hanpu Science & Education District, Changsha 410208, Hunan, China. Electronic address: dfliao66@aliyun.com.
authors.forename: Duan-fang
authors.initials: DF
authors.lastname: Liao
mesh_terms: D050171:Dyslipidemias / Q000188:drug therapy* / Q000378:metabolism*; D006801:Humans; D000960:Hypolipidemic Agents / Q000008:administration & dosage*; D008954:Models, Biological; D011973:Receptors, LDL / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000187:drug effects / Q000378:metabolism*
chemical_list: D000960:Hypolipidemic Agents; D011973:Receptors, LDL; C403126:MYLIP protein, human; D044767:Ubiquitin-Protein Ligases