Ndoj Klevis, Meurs Amber, Papaioannou Dimitra, Bjune Katrine, Zelcer Noam
Department of Medical Biochemistry, Amsterdam UMC Location AMC, University of Amsterdam, Meibergdreef 9, 1105AZ, Amsterdam, the Netherlands; Amsterdam Gastroenterology Endocrinology Metabolism (AGEM) Institute, Amsterdam UMC, Meibergdreef 9, 1105AZ, Amsterdam, the Netherlands; Amsterdam Cardiovascular Sciences (ACS) Institute, Amsterdam UMC, Meibergdreef 9, 1105AZ, Amsterdam, the Netherlands.
Department of Medical Biochemistry, Amsterdam UMC Location AMC, University of Amsterdam, Meibergdreef 9, 1105AZ, Amsterdam, the Netherlands.
Atherosclerosis. 2025 Feb;401:119082. doi: 10.1016/j.atherosclerosis.2024.119082. Epub 2024 Dec 5.
Cholesterol is a vital component of cellular membranes and is an essential molecule in mammalian physiology. Yet dysregulation of hepatic cholesterol metabolism and an increase in plasma cholesterol is linked to development of atherosclerotic cardiovascular disease. Maintaining tight regulation of cholesterol homeostasis is therefore essential, elegantly highlighted by the control of hepatic low-density lipoprotein receptor (LDLR) abundance and associated lipoprotein clearance. The LDLR was discovered in the 1970's in the seminal work of Brown and Goldstein. This was followed by the development of statins, which promote hepatic clearance of LDL via the LDLR pathway. The discovery two decades ago of Proprotein Convertase Subtilisin-Kexin Type 9 (PCSK9), a secreted protein that binds to the LDLR ectodomain and promotes its degradation, and the clinical development of PCSK9 inhibitors has ushered an effort to uncover additional mechanisms that govern the function and abundance of the LDLR. In recent years this has led to the identification of novel post-transcriptional and post-translational mechanisms that govern the LDLR. This review focuses on these emerging regulatory mechanisms and specifically discusses: (1) Regulation of the LDLR mRNA by RNA-binding proteins and microRNAs, (2) Ubiquitin-dependent degradation of the LDLR protein by the E3 ubiquitin ligases inducible degrader of the LDLR (IDOL) and GOLIATH (RNF130), (3) Control of the LDLR pathway by the asialoglycoprotein receptor 1 (ASGR1), and (4) The role of LDLR ectodomain shedding mediated by membrane-type 1 matrix metalloprotease (MT1-MMP), Bone morphogenetic protein 1 (BMP1), and γ-secretase. Understanding the contribution of these emerging mechanisms to regulation of the LDLR is important for the development of novel LDLR-focused lipid-lowering strategies.
胆固醇是细胞膜的重要组成部分，也是哺乳动物生理学中的必需分子。然而，肝脏胆固醇代谢失调和血浆胆固醇升高与动脉粥样硬化性心血管疾病的发生有关。因此，维持胆固醇稳态的严格调控至关重要，肝脏低密度脂蛋白受体（LDLR）丰度的控制及相关脂蛋白清除率就很好地体现了这一点。LDLR于20世纪70年代在Brown和Goldstein的开创性研究中被发现。随后他汀类药物得以开发，其通过LDLR途径促进肝脏对LDL的清除。二十年前发现了前蛋白转化酶枯草溶菌素9型（PCSK9），这是一种分泌蛋白，可与LDLR胞外域结合并促进其降解，PCSK9抑制剂的临床开发促使人们努力揭示调控LDLR功能和丰度的其他机制。近年来，这导致了调控LDLR的新的转录后和翻译后机制的发现。本综述聚焦于这些新出现的调控机制，并具体讨论：（1）RNA结合蛋白和微小RNA对LDLR mRNA的调控，（2）E3泛素连接酶LDLR诱导降解物（IDOL）和歌利亚蛋白（RNF130）对LDLR蛋白的泛素依赖性降解，（3）去唾液酸糖蛋白受体1（ASGR1）对LDLR途径的控制，以及（4）膜型1基质金属蛋白酶（MT1-MMP）、骨形态发生蛋白1（BMP1）和γ-分泌酶介导的LDLR胞外域脱落的作用。了解这些新出现的机制对LDLR调控的贡献，对于开发以LDLR为重点的新型降脂策略很重要。
