Downregulation of lncRNA EPB41L4A-AS1 Mediates Activation of MYD88-Dependent NF-κB Pathway in Diabetes-Related Inflammation.
Downregulation of lncRNA EPB41L4A-AS1 Mediates Activation of MYD88-Dependent NF-κB Pathway in Diabetes-Related Inflammation.
复制标题
lncRNA EPB4IL4A-ASI 的下调介导糖尿病相关炎症中 MYD88 依赖性 NF-kappa B 通路的激活
DOI：
10.2147/dmso.s280765
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Zhang Y
中科院分区：
文献类型：
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作者：
Wang Z;Liao W;Liu F;Yang T;Xie W;Liao M;Gu D;Zhang Y
长非编码RNA(LncRNAs)已被证明与许多人类疾病有关。本研究旨在揭示lncRNA EPB41L4A-AS1在2型糖尿病(T2 DM)相关炎症中的作用及其分子机制。为了探讨EPB41L4A-AS1在T2 DM患者血液中的表达与炎症因子的关系，我们从GEO数据库中分析了T2 DM患者外周血单个核细胞(PBMC)的表达芯片和脂多糖(LPS)处理的PBMC的表达芯片。用Western blotting和免疫荧光方法探讨EPB41L4A-AS1与磷酸化p65的关系。通过实时定量聚合酶链式反应、免疫印迹和染色质免疫沉淀证实EPB41L4A-AS1与髓系分化因子88(MYD88)的相互作用。海马细胞检测糖酵解和线粒体应激反应。EPB41L4A-AS1在T2 DM患者和脂多糖处理的PBMC中低表达，与炎症因子水平呈显著负相关。在PBMC和THP-1细胞上的细胞实验验证了这些结果。EPB41L4A-AS1基因的敲除导致p65的磷酸化和核转位，从而激活了NF-κB信号通路；它还减少了H3K9me3在MYD88启动子中的浓缩，增加了MYD88的表达。总体而言，EPB41L4A-AS1基因敲除促进了糖酵解水平，并最终增强了炎症反应。EPB41L4A-AS1基因敲除通过依赖MYD88的调节机制激活了NF-κB信号通路，促进了糖酵解，最终增强了炎症反应。这些结果表明EPB41L4A-AS1与T2 DM的炎症密切相关，EPB41L4A-AS1的低表达可作为T2 DM患者慢性炎症和可能的糖尿病血管并发症的指标。
Long non-coding RNAs (lncRNAs) have been shown to be involved in many human diseases. In this study, we aimed to reveal the role and molecular mechanism of lncRNA EPB41L4A-AS1 in type 2 diabetic mellitus (T2DM)-related inflammation. To explore the relationships between the expression of EPB41L4A-AS1 and inflammatory factors in the blood of T2DM patients, we analyzed peripheral blood mononuclear cell (PBMC) expression microarrays of T2DM patients and expression microarrays of PBMC treated with lipopolysaccharide (LPS) from the GEO database. The relationship between EPB41L4A-AS1 and phospho-p65 was explored by Western blotting (WB) and immunofluorescence. The interactions between EPB41L4A-AS1 and myeloid differentiation factor 88 (MYD88) were also verified through quantitative real-time PCR, WB, and chromatin immunoprecipitation. Glycolysis and mitochondrial stress were detected by Seahorse. EPB41L4A-AS1 showed very low expression, which was significantly negatively correlated with levels of inflammatory factors in PBMCs of T2DM patients and PBMCs treated with LPS. These results were verified by cell experiments on PBMC and THP-1 cells. Knockdown of EPB41L4A-AS1 led to the phosphorylation and nuclear translocation of p65 and thus activated the NF-κB signaling pathway; it also reduced the enrichment of H3K9me3 in the MYD88 promoter and increased expression of MYD88. Overall, EPB41L4A-AS1 knockdown promoted the level of glycolysis and ultimately enhanced the inflammatory response. EPB41L4A-AS1 knockdown activated the NF-κB signaling pathway through a MYD88-dependent regulatory mechanism, promoted glycolysis, and ultimately enhanced the inflammatory response. These results demonstrate that EPB41L4A-AS1 is closely associated with inflammation in T2DM, and that low expression of EPB41L4A-AS1 may be used as an indicator of chronic inflammation and possible diabetic vascular complications in T2DM patients.