Comprehensive Analysis of the Expression Profiles of Hepatic lncRNAs in the Mouse Model of Alcoholic Liver Disease.
Comprehensive Analysis of the Expression Profiles of Hepatic lncRNAs in the Mouse Model of Alcoholic Liver Disease.
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酒精性肝病小鼠模型中肝脏 lncRNA 表达谱的综合分析。
DOI：
10.3389/fphar.2021.709287
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发表时间：
2021
影响因子：
5.6
通讯作者：
Li S
中科院分区：
文献类型：
--
作者：
Dou X;Yang W;Ding Q;Han Q;Qian Q;Du Z;Fan Y;Wang C;Li S
背景与目的：酒精性肝病（ALD）在世界范围内的流行是由于不断增加的酒精消费给人类健康带来了前所未有的压力。一些研究已经确定了长链非编码rna （lncRNAs）参与肝脏疾病的发病机制。然而，lncrna在ALD发展中的作用仍然知之甚少。方法：建立ALD小鼠模型并进行验证。通过全转录组测序获得lncrna的表达谱。通过qRT-PCR进一步验证ALD小鼠中lncrna的改变。使用基因本体（GO）和京都基因与基因组百科全书（KEGG）富集分析来丰富这些lncrna的功能。结合miRNA和mRNA谱，我们构建了简洁的内源性RNA （ceRNA）网络。在ALD模型和AML-12细胞中进一步验证和研究了上调/下调最多的lnRNA的功能。结果：共获得5个下调lncrna，并在ALD小鼠中得到验证。GO术语和KEGG通路分析显示，鉴定的lncrna与酒精诱导的肝脏氧化损伤、细胞炎症和脂质代谢有关。将差异调制的mirna和mrna与ceRNA网络分析相结合，我们构建了5个ceRNA网络，获得了30个可能参与ALD的mirna和25个mrna。进一步，我们验证并研究了下调最多的lnc_1700023H06Rik的功能。lnc_1700023H06Rik在体内和体外均减少了编码脂质代谢的基因，特别是mRNA Acat2 （ENSMUST00000159697）和Pgrmc2 （ENSMUST00000058578）。敲除lnc_1700023H06Rik诱导AML12细胞中甘油三酯积累和乳酸脱氢酶渗漏，与酒精处理细胞中相同。结论：ALD小鼠模型中5个显著下调的lncRNAs被鉴定为新的生物标志物，突出了lncRNAs在ALD发生发展中的关键作用。lnc_1700023H06Rik在脂质沉积中起关键作用，其在ALD中的病理途径有待进一步研究。
Background and Aim: The worldwide prevalence of alcoholic liver disease (ALD) due to escalating alcohol consumption has presented an unprecedented pressure on human health. A few studies have determined long non-coding RNAs (lncRNAs) involved in the pathogenesis of liver diseases. However, the roles of lncRNAs in ALD development is still poorly understood. Methods: An ALD mouse model was established and confirmed. Expression profiles of lncRNAs were obtained by whole transcriptome sequencing. The altered lncRNAs in ALD mice were further verified by qRT-PCR. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were used to enrich the functions of these lncRNAs. In combination with miRNA and mRNA profiles, we constructed concise endogenous RNA (ceRNA) networks. The function of the most up/downregulated lnRNA was further verified and investigated in both ALD model and AML-12 cells. Results: Totally, five downregulated lncRNAs were obtained and verified in ALD mice. The GO term and KEGG pathway analyses revealed that the identified lncRNAs were associated with alcohol-induced hepatic oxidative damage, cellular inflammation, and lipid metabolism. Combination the differentially modulated miRNAs and mRNAs with ceRNA network analysis, we constructed five ceRNA networks and obtained 30 miRNAs and 25 mRNAs that may participate in ALD. Further, we verified and investigate the function of the most downregulated lnc_1700023H06Rik. Depletion lnc_1700023H06Rik reduced genes encoding for lipid metabolism, especially mRNA Acat2 (ENSMUST00000159697) and Pgrmc2 (ENSMUST00000058578) both in vivo and in vitro. Knocking down lnc_1700023H06Rik induced triglyceride accumulation and lactate dehydrogenase leakage in AML12 cells, consisting with that in alcohol-treated cells. Conclusion: The five remarkably downregulated lncRNAs in ALD mouse model were identified as novel biomarkers, highlighting the key role of lncRNAs in the development of ALD. The effect of lnc_1700023H06Rik plays a pivotal role in lipid deposition and its pathological pathway in ALD needs further investigation.
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DOI：
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发表时间：
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期刊：
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影响因子：
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