MicroRNA在胆固醇逆转运中的调节作用

胆固醇逆转运是体内清除胆固醇的唯一机制,对维持体内胆固醇稳态有重要意义。MicroRNA与体内诸多病理生理过程关系密切,如肿瘤、脂质代谢、免疫功能等,并逐渐成为新的药物靶点。最近发现MicroRNA对胆固醇逆转运有调节作用。本文综述了可调节胆固醇逆转运的MicroRNA,主要包括miR-33、miR-758、miR-106b、miR-26、miR-27。这些研究结果表明,MicroRNA对胆固醇逆转运及动脉粥样硬化有重要意义,为临床防止动脉粥样硬化提供新的药物靶点。     

ABCA1表达的microRNA转录后水平调控

胆固醇逆转运(RCT)是体内清除胆固醇的重要机制,对维持体内胆固醇稳态,预防动脉粥样硬化有着重要意义。ATP结合盒转运体A1(ABCA1)是胆固醇逆转运过程中的关键因子,ABCA1的表达受到转录水平和转录后水平的多种因素调控,其中microRNA介导ABCA1表达的转录后水平调控备受重视。近年来的研究发现,多种microRNA能直接以ABCA1为靶基因调控ABCA1的表达,同时也发现一些microRNA通过作用于调控ABCA1基因的转录因子间接发挥效应,如肝X受体α(LXRα)、过氧化体增殖物激活型受体γ(PPARγ)、视黄醇类核内受体α(RXRα)等间接调控ABCA1的表达,从而达到影响胆固醇流出的目的。这些microRNA包括miR-33a/b、miR-19b、miR-27a/b、miR-302、miR-758及miR-106b等。本文主要综述已知microRNA对ABCA1表达的影响。     

循环微小RNA早期诊断心肌梗死研究进展

<正>微小RNA(microRNA,miRNA)是一类调控基因表达,高度保守的非编码miRNA(21～24nt),参与多种信号通路的调节,在维持内环境稳态中发挥重要作用[1]。从细胞分泌到外周血的miRNA称为循环miRNA,它们在正常人和各种疾病患者体内的表达谱存在明显的差异,并且稳定的存在于外周血中,从而具有诊断相关疾病的内在潜能[2]。作为     

胆固醇稳态与微小RNA的调节

<正>体内胆固醇的代谢由多种蛋白共同参与,并受多因素调控,各因素协调作用保证了胆固醇的稳态。近年研究表明,微小RNA(microRNA,miRNA)通过调控胆固醇代谢中关键蛋白的表达,在维持胆固醇稳态中发挥着重要作用。我们首先从胆固醇的来源、转运及分解代谢3个方面对胆固醇稳态进行论述,并对miRNA调控胆固醇稳态的研究进展做一综述。1胆固醇稳态1.1胆固醇的来源人体内胆固醇的来源靠从食物中摄取     

靶向肝X受体的抗动脉粥样硬化药物研究进展

肝X受体(LXR)是机体胆固醇稳态维持的重要调控因子,通过调控下游靶基因表达,参与调节各组织中的胆固醇代谢。LXR激动剂能够促进胆固醇逆向转运,发挥抗动脉粥样硬化作用,具有潜在治疗心血管疾病的作用。本文围绕近年来新型LXR激动剂,从不同来源、特点和作用机制等角度对其发挥抗动脉粥样硬化作用进行综述。     

miRNA 调控脂质代谢的相关研究进展

miRNA是一种能负性调节基因表达非蛋白编码单链RNA,能够特异性结合到对应的mRNA上并使其翻译受到抑制。目前已发现一些miRNA与脂质代谢密切相关,特别是miR-122和miR-33对脂质谢的稳态有重要影响,甚至可成为治疗脂代谢与动脉粥样硬化相关疾病的潜在靶标。本文总结近期有关miRNA在调节脂代谢方面的研究,旨在为其相关机制更进一步的研究提供参考。     

参与负性调控胆固醇逆向转运的microRNA

加强胆固醇逆向转运(RCT)具有抗动脉粥样硬化作用,microRNA(miRNA)参与多种生物学过程的调控,研究发现多个miRNA参与RCT调控,其通过对RCT的关键蛋白ATP结合盒转运体A1(ABCA1)和受体B类Ⅰ型清道夫受体(SR-BⅠ)的调控而发挥作用。目前已发现多种miRNA可抑制ABCA1和SR-BⅠ蛋白表达水平,进而抑制RCT和胆固醇流出,本文拟就负性调控RCT的miRNA进行综述。     

低密度脂蛋白受体及其调节机制研究进展

冠状动脉疾病其发病率在绝经后大大增加,血浆低密度脂蛋白胆固醇水平被认为是心血管疾病发生的主要的危险因子。低密度脂蛋白受体对维持体内胆固醇稳态以及对调节肝脏对低密度脂蛋白胆固醇代谢方面发挥重要作用。低密度脂蛋白受体基因突变可以导致低密度脂蛋白受体功能异常和家族性高胆固醇血症。上调低密度脂蛋白受体的表达可以降低血浆低密度脂蛋白胆固醇水平,降低心血管意外的发生率。低密度脂蛋白受体基因的表达受到许多因素在转录水平和转录后水平的调节。本文主要对低密度脂蛋白受体基因表达调节机制的研究进展进行阐述。     

维持体内胆固醇稳态的重要膜蛋白

正胆固醇是人体中必不可少的物质,体内胆固醇含量过高会引起动脉粥样硬化性心血管疾病及脂质代谢异常相关疾病,含量过低可引起血管脆性增加、激素缺乏、免疫力下降及癌症发病率增高等病理过程,因此,维持体内胆固醇稳态对人体健康至关重要~([1])。人体内胆固醇代谢受多方面的调节,包括自身合成、小肠吸收、胆汁分泌、粪便排泄,其中一些膜蛋白在过程中发挥重要作用。1维持消化道胆固醇稳态的重要膜蛋白体内胆固醇主要是通过肝脏合成和肠道吸收两种途径     

淋巴管参与胆固醇逆向转运

细胞需要胆固醇才能生存,但过量的胆固醇对细胞具有毒性,因此细胞需要调节胆固醇的稳态。细胞内胆固醇被转运到高密度脂蛋白载脂蛋白AI,会以胆固醇逆向转运的方式返回肝脏代谢。胆固醇逆向转运不仅是维持细胞胆固醇稳态所需的生理过程,而且对动脉粥样硬化发展起到潜在的抑制作用。目前的研究主要集中在细胞胆固醇流出的最初途径和最终代谢上,但关于胆固醇是如何离开血液却知之甚少。越来越多的研究表明,在胆固醇逆向转运过程中高密度脂蛋白需要通过淋巴管转运以返回到肝脏代谢。因此,研究高密度脂蛋白从血液流入外周组织的过程,以及它是怎样通过淋巴管转运对治疗动脉粥样硬化具有重要意义。本综述主要介绍淋巴管与胆固醇逆向转运之间的联系,为治疗动脉粥样硬化性心血管疾病提供新的策略。     

miR-33a/b contribute to the regulation of fatty acid metabolism and insulin signaling

Cellular imbalances of cholesterol and fatty acid metabolism result in pathological processes, including atherosclerosis and metabolic syndrome. Recent work from our group and others has shown that the intronic microRNAs hsa-miR-33a and hsa-miR-33b are located within the sterol regulatory element-binding protein-2 and -1 genes, respectively, and regulate cholesterol homeostasis in concert with their host genes. Here, we show that miR-33a and -b also regulate genes involved in fatty acid metabolism and insulin signaling. miR-33a and -b target key enzymes involved in the regulation of fatty acid oxidation, including carnitine O-octaniltransferase, carnitine palmitoyltransferase 1A, hydroxyacyl-CoA-dehydrogenase, Sirtuin 6 (SIRT6), and AMP kinase subunit-α. Moreover, miR-33a and -b also target the insulin receptor substrate 2, an essential component of the insulin-signaling pathway in the liver. Overexpression of miR-33a and -b reduces both fatty acid oxidation and insulin signaling in hepatic cell lines, whereas inhibition of endogenous miR-33a and -b increases these two metabolic pathways. Together, these data establish that miR-33a and -b regulate pathways controlling three of the risk factors of metabolic syndrome, namely levels of HDL, triglycerides, and insulin signaling, and suggest that inhibitors of miR-33a and -b may be useful in the treatment of this growing health concern.     

MicroRNA-185-5p mediates regulation of SREBP2 expression by hepatitis C virus core protein

AIM: To investigate the molecular mechanism for regulation of cholesterol metabolism by hepatitis C virus (HCV) core protein in HepG2 cells.METHODS: HCV genotype 1b core protein was cloned and expressed in HepG2 cells. The cholesterol content was determined after transfection. The expression of sterol regulatory element binding protein 2 (SREBP2) and the rate-limiting enzyme in cholesterol synthesis (HMGCR) was measured by quantitative real-time PCR and immunoblotting after transfection. The effects of core protein on the SREBP2 promoter and 3’-untranslated region were analyzed by luciferase assay. We used different target predictive algorithms, microRNA (miRNA) mimics/inhibitors, and site-directed mutation to identify a putative target of a particular miRNA.RESULTS: HCV core protein expression in HepG2 cells increased the total intracellular cholesterol level (4.05 ± 0.17 vs 6.47 ± 0.68, P = 0.001), and this increase corresponded to an increase in SREBP2 and HMGCR mRNA levels (P = 0.009 and 0.037, respectively) and protein expression. The molecular mechanism study revealed that the HCV core protein increased the expression of SREBP2 by enhancing its promoter activity (P = 0.004). In addition, miR-185-5p expression was tightly regulated by the HCV core protein (P = 0.041). Moreover, overexpression of miR-185-5p repressed the SREBP2 mRNA level (P = 0.022) and protein expression. In contrast, inhibition of miR-185-5p caused upregulation of SREBP2 protein expression. miR-185-5p was involved in the regulation of SREBP2 expression by HCV core protein.CONCLUSION: HCV core protein disturbs the cholesterol homeostasis in HepG2 cells via the SREBP2 pathway; miR-185-5p is involved in the regulation of SREBP2 by the core protein.     

MicroRNAs regulate critical genes associated with multiple myeloma pathogenesis

Progress in understanding the biology of multiple myeloma (MM), a plasma cell malignancy, has been slow. The discovery of microRNAs (miRNAs), a class of small noncoding RNAs targeting multiple mRNAs, has revealed a new level of gene expression regulation. To determine whether miRNAs play a role in the malignant transformation of plasma cells (PCs), we have used both miRNA microarrays and quantitative real time PCR to profile miRNA expression in MM-derived cell lines (n = 49) and CD138+ bone marrow PCs from subjects with MM (n = 16), monoclonal gammopathy of undetermined significance (MGUS) (n = 6), and normal donors (n = 6). We identified overexpression of miR-21, miR-106b approximately 25 cluster, miR-181a and b in MM and MGUS samples with respect to healthy PCs. Selective up-regulation of miR-32 and miR-17 approximately 92 cluster was identified in MM subjects and cell lines but not in MGUS subjects or healthy PCs. Furthermore, two miRNAs, miR-19a and 19b, that are part of the miR-17 approximately 92 cluster, were shown to down regulate expression of SOCS-1, a gene frequently silenced in MM that plays a critical role as inhibitor of IL-6 growth signaling. We also identified p300-CBP-associated factor, a gene involved in p53 regulation, as a bona fide target of the miR106b approximately 25 cluster, miR-181a and b, and miR-32. Xenograft studies using human MM cell lines treated with miR-19a and b, and miR-181a and b antagonists resulted in significant suppression of tumor growth in nude mice. In summary, we have described a MM miRNA signature, which includes miRNAs that modulate the expression of proteins critical to myeloma pathogenesis.     

MicroRNAs in vascular and metabolic disease

Recent findings demonstrated the importance of microRNAs (miRNAs) in the vasculature and the orchestration of lipid metabolism and glucose homeostasis. MiRNA networks represent an additional layer of regulation for gene expression that absorbs perturbations and ensures the robustness of biological systems. This function is very elegantly demonstrated in cholesterol metabolism where miRNAs reducing cellular cholesterol export are embedded in the very same genes that increase cholesterol synthesis. Often their alteration does not affect normal development but changes under stress conditions and in disease. A detailed understanding of the molecular and cellular mechanisms of miRNA-mediated effects on metabolism and vascular pathophysiology could pave the way for the development of novel diagnostic markers and therapeutic approaches. In the first part of this review, we summarize the role of miRNAs in vascular and metabolic diseases and explore potential confounding effects by platelet miRNAs in preclinical models of cardiovascular disease. In the second part, we discuss experimental strategies for miRNA target identification and the challenges in attributing miRNA effects to specific cell types and single targets.