Mechanistic Role of MicroRNAs in Coupling Lipid Metabolism and Atherosclerosis.
Mechanistic Role of MicroRNAs in Coupling Lipid Metabolism and Atherosclerosis.
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DOI：
10.1007/978-3-319-22380-3_5
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发表时间：
2015
影响因子：
--
通讯作者：
Santulli G
中科院分区：
文献类型：
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作者：
Novák J;Olejníčková V;Tkáčová N;Santulli G
microRNAs（miRNAs，miRs）是一类功能强大、功能多样的基因表达转录后调控因子，参与了多种生理和病理过程的精细调控。除了在细胞周期、胚胎发生或肿瘤发生的调节中发挥公认的关键作用外，这些微小分子还被证明参与脂质代谢的调节。特别是，miR协调胆固醇和脂肪酸的合成、转运和降解以及低密度和高密度脂蛋白（LDL和HDL）的形成。因此，据报道它们也影响几种脂质代谢相关疾病（包括肝脂肪变性和动脉粥样硬化）的发生和进展，这并不奇怪。越来越多的证据表明，miR可能代表脂质代谢的重要“转录后枢纽”，这意味着一个miR通常靶向参与一个精确代谢/信号传导途径的不同步骤的各种mRNA的3′-非翻译区，例如，一种miR靶向对胆固醇合成、降解和转运重要的酶的mRNA。因此，一种关键miR水平的变化影响一种途径的各个步骤，从而促进或抑制该途径。这使得miRs成为未来个性化医疗的有效诊断甚至治疗工具。在本章中，涉及脂质代谢的最突出的microRNA，例如，miR-27 a/B、miR-33/33*、miR-122、miR-144或miR-223及其细胞内和细胞外功能将被广泛讨论，特别关注它们在动脉粥样硬化病理生理学中的机制作用。将特别强调miR-122，目前在临床试验中用于治疗丙型肝炎的第一个microRNA和miR-223，脂蛋白颗粒中最丰富的miR。
MicroRNAs (miRNAs, miRs) represent a group of powerful and versatile posttranscriptional regulators of gene expression being involved in the fine control of a plethora of physiological and pathological processes. Besides their well-established crucial roles in the regulation of cell cycle, embryogenesis or tumorigenesis, these tiny molecules have also been shown to participate in the regulation of lipid metabolism. In particular, miRs orchestrate cholesterol and fatty acids synthesis, transport, and degradation and low-density and high-density lipoprotein (LDL and HDL) formation. It is thus not surprising that they have also been reported to affect the development and progression of several lipid metabolism-related disorders including liver steatosis and atherosclerosis. Mounting evidence suggests that miRs might represent important “posttranscriptional hubs” of lipid metabolism, which means that one miR usually targets 3′-untranslated regions of various mRNAs that are involved in different steps of one precise metabolic/signaling pathway, e.g., one miR targets mRNAs of enzymes important for cholesterol synthesis, degradation, and transport. Therefore, changes in the levels of one key miR affect various steps of one pathway, which is thereby promoted or inhibited. This makes miRs potent future diagnostic and even therapeutic tools for personalized medicine. Within this chapter, the most prominent microRNAs involved in lipid metabolism, e.g., miR-27a/b, miR-33/33*, miR-122, miR-144, or miR-223, and their intracellular and extracellular functions will be extensively discussed, in particular focusing on their mechanistic role in the pathophysiology of atherosclerosis. Special emphasis will be given on miR-122, the first microRNA currently in clinical trials for the treatment of hepatitis C and on miR-223, the most abundant miR in lipoprotein particles.