Objective

Long noncoding RNAs (lncRNAs) are currently considered to have a vital and wide range of biological functions, but the molecular mechanism underlying triglycerides metabolism remains poorly understood. This study aims to identify novel lncRNAs differentially expressed in rat livers with hypertriglyceridemia and elucidated the function role in TG metabolism.

Methods

Differentially expressions of lncRNAs in rat livers with hypertriglyceridemia were identified by transcriptome sequencing and validated by real-time PCR. The role of lnc19959.2 in triglyceride metabolism was assessed both in vitro and in vivo. RNA pulldown and RIP assays were conducted to evaluate the interactions between lnc19959.2 and its target proteins. ChIP and Dual report assays were performed to detect the interactions between transcription factors and promoters of its target genes.

Results

We identified a novel lncRNA, and lnc19959.2 was upregulated in rat livers with hypertriglyceridemia. The knockdown of lnc19959.2 has profound TG lowering effects in vitro and in vivo. Subsequently, the genome-wide analysis identified that the knockdown of lnc19959.2 caused the deregulation of many genes during TG homeostasis. Further mechanism studies revealed that lnc19959.2 upregulated ApoA4 expression via ubiquitinated transcription inhibitor factor Purb, while it specifically interacted with hnRNPA2B1 to downregulate the expression of Cpt1a, Tm7sf2, and Gpam, respectively. In the upstream pathway, palmitate acid upregulated CCAAT/Enhancer-Binding Protein Beta (Cebpb) and facilitated its binding to the promoter of lnc19959.2, which resulted in significant promotion of lnc19959.2 transcriptional activity.

Conclusions

Our findings provide novel insights into a new layer regulatory complexity of an lncRNA modulating triglyceride homeostasis by a novel lncRNA lnc19959.2.

中文翻译：

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新型长非编码RNA Lnc19959.2通过与Purb和hnRNPA2B1的相互作用调节甘油三酸酯代谢相关基因。

目的

长非编码RNA（lncRNA）当前被认为具有重要而广泛的生物学功能，但是甘油三酸酯代谢的分子机制仍然知之甚少。这项研究旨在鉴定高甘油三酸酯血症大鼠肝脏中差异表达的新型lncRNA，并阐明其在TG代谢中的功能。

方法

通过转录组测序鉴定了高甘油三酯血症大鼠肝脏中lncRNA的差异表达，并通过实时PCR进行了验证。在体外和体内均评估了lnc19959.2在甘油三酸酯代谢中的作用。进行了RNA下拉和RIP分析，以评估lnc19959.2及其靶蛋白之间的相互作用。进行了ChIP和Dual report分析，以检测转录因子与其靶基因启动子之间的相互作用。

结果

我们鉴定了一种新的lncRNA，并且在患有高甘油三酯血症的大鼠肝脏中lnc19959.2被上调。击倒lnc19959。2具有深刻的TG降低作用的体外和体内。随后，全基因组分析确定lnc19959.2的敲低导致TG稳态期间许多基因的失调。进一步机制研究揭示，lnc19959.2上调APOA4经由泛素化的转录抑制剂因子表达PURB，虽然它特别与之交互hnRNPA2B1下调的表达CPT1A，Tm7sf2，和Gpam。在上游途径中，棕榈酸上调CCAAT /增强子结合蛋白β（Cebpb）并促进其与lnc19959.2启动子的结合，从而显着促进lnc19959.2转录活性。

结论

我们的发现为通过新型lncRNA lnc19959.2调节甘油三酯稳态的lncRNA的新层调节复杂性提供了新颖的见解。