Long Non-Coding RNA Profiling in a Non-Alcoholic Fatty Liver Disease Rodent Model: New Insight into Pathogenesis.
Long Non-Coding RNA Profiling in a Non-Alcoholic Fatty Liver Disease Rodent Model: New Insight into Pathogenesis.
复制标题
非酒精性脂肪性肝病啮齿动物模型中的长非编码 RNA 分析：发病机制的新见解
DOI：
10.3390/ijms18010021
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发表时间：
2017-01-16
影响因子：
5.6
通讯作者：
Li Y
中科院分区：
文献类型：
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作者：
Chen Y;Huang H;Xu C;Yu C;Li Y
非酒精性脂肪性肝病（NAFLD）是世界范围内最常见的慢性肝病之一，其发病机制尚不清楚。长链非编码RNA（longnon-codingRNA，lncRNA）是近年来出现的重要调控分子。为了更好地理解NAFLD发病机制，在NAFLD啮齿动物模型中进行lncRNA和信使RNA（mRNA）微阵列。使用顺式/反式调节算法预测显著改变的lncRNA的潜在靶基因。然后进行基因本体（GO）分析和京都基因和基因组百科全书（KEGG）途径富集分析以探索它们的功能。在目前的分析中，鉴定了89种上调和177种下调的mRNA，以及291种去调控的lncRNA。对这些RNA的生物信息学分析已将这些RNA归类为包括花生四烯酸代谢、昼夜节律、亚油酸代谢、过氧化物酶体增殖物激活受体（PPAR）信号通路、鞘脂代谢、类固醇生物合成、色氨酸代谢和酪氨酸代谢在内的途径。对代表性的9种mRNA和8种lncRNA（称为脂肪肝相关lncRNA，FLRL）进行定量聚合酶链反应（qPCR），这验证了先前的微阵列结果。FLRL 1、FLRL 6和FLRL 2等lncRNA分别参与了以周期生物钟3（Per 3）、Per 2和芳香烃受体核转位因子样（Arntl）为靶点的生物节律调控。FLRL 8、FLRL 3和FLRL 7通过与脂肪酸结合蛋白5（Fabp 5）、脂蛋白脂酶（Lpl）和脂肪酸去饱和酶2（Fads 2）相互作用而在PPAR信号通路中发挥作用。功能实验表明，干扰lncRNA FLRL 2的表达影响预测的目标，昼夜节律基因Arntl的表达。此外，FLRL 2和Arntl在NAFLD细胞模型中均下调。目前的研究确定了lncRNA和相应的mRNA在NAFLD，提供了新的见解NAFLD的发病机制。此外，我们还发现了一个新的lncRNA FLRL 2，它可能参与了Arntl介导的NAFLD发病机制。
Non-alcoholic fatty liver disease (NAFLD) is one of the most prevalent chronic liver diseases worldwide with an unclear mechanism. Long non-coding RNAs (lncRNAs) have recently emerged as important regulatory molecules. To better understand NAFLD pathogenesis, lncRNA and messenger RNA (mRNA) microarrays were conducted in an NAFLD rodent model. Potential target genes of significantly changed lncRNA were predicted using cis/trans-regulatory algorithms. Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were then performed to explore their function. In the current analysis, 89 upregulated and 177 downregulated mRNAs were identified, together with 291 deregulated lncRNAs. Bioinformatic analysis of these RNAs has categorized these RNAs into pathways including arachidonic acid metabolism, circadian rhythm, linoleic acid metabolism, peroxisome proliferator-activated receptor (PPAR) signaling pathway, sphingolipid metabolism, steroid biosynthesis, tryptophan metabolism and tyrosine metabolism were compromised. Quantitative polymerase chain reaction (qPCR) of representative nine mRNAs and eight lncRNAs (named fatty liver-related lncRNA, FLRL) was conducted and this verified previous microarray results. Several lncRNAs, such as FLRL1, FLRL6 and FLRL2 demonstrated to be involved in circadian rhythm targeting period circadian clock 3 (Per3), Per2 and aryl hydrocarbon receptor nuclear translocator-like (Arntl), respectively. While FLRL8, FLRL3 and FLRL7 showed a potential role in PPAR signaling pathway through interaction with fatty acid binding protein 5 (Fabp5), lipoprotein lipase (Lpl) and fatty acid desaturase 2 (Fads2). Functional experiments showed that interfering of lncRNA FLRL2 expression affected the expression of predicted target, circadian rhythm gene Arntl. Moreover, both FLRL2 and Arntl were downregulated in the NAFLD cellular model. The current study identified lncRNA and corresponding mRNA in NAFLD, providing new insight into the pathogenesis of NAFLD. Moreover, we identified a new lncRNA FLRL2, that might participate NAFLD pathogenesis mediated by Arntl.