Serum miR-379 expression is related to the development and progression of hypercholesterolemia in non-alcoholic fatty liver disease
Serum miR-379 expression is related to the development and progression of hypercholesterolemia in non-alcoholic fatty liver disease
复制标题
DOI：
10.1371/journal.pone.0219412
复制
发表时间：
2020-02-27
期刊：
影响因子：
3.7
通讯作者：
Isomoto, Hajime
中科院分区：
文献类型：
--
作者：
Okamoto, Kinya;Koda, Masahiko;Isomoto, Hajime
前言非酒精性脂肪性肝病（NAFLD）具有广泛的发病谱，最终可导致肝硬化和肝癌。我们先前报道了一系列定位于14q32.2母系印记基因区域（Dlk 1-Dio 3 mat）的microRNA（miRNAs）与小鼠模型中NAFLD的发生和进展相关。我们研究了miR-379，一种循环Dlk 1-Dio 3 mat miRNA，作为人类NAFLD生物标志物的适用性。miR-379是从假定的Dlk 1-Dio 3 mat miRNA簇中选择的，因为在我们的初步研究中，它在NAFLD和非酒精性脂肪性肝炎之间表现出最大的表达差异。使用实时PCR检测miR-379和miR-16的表达水平作为内部对照。结果与正常对照组相比，NAFLD患者血清中miR-379表达显著上调。受试者工作特征曲线分析表明，miR-379是区分NAFLD患者和对照的合适标志物，曲线下面积值为0.72。血清miR-379与早期NAFLD患者（Brunt纤维化0 - 1期）的碱性磷酸酶、总胆固醇、低密度脂蛋白胆固醇和非高密度脂蛋白胆固醇水平呈正相关。在接受他汀类药物治疗的早期NAFLD患者中，血清miR-379和胆固醇水平之间的相关性丢失。基于软件的预测结果表明，多种能量代谢相关基因，包括胰岛素样生长因子-1（IGF-1）和IGF-1受体，都是miR-379的潜在靶点。miR-379似乎增加胆固醇脂毒性，导致NAFLD的发展和进展，通过干扰靶基因的表达，包括与IGF-1信号通路相关的基因。我们的研究结果将有助于进一步研究NAFLD的发病机制、诊断和治疗。
IntroductionNon-alcoholic fatty liver disease (NAFLD) has a wide spectrum, eventually leading to cirrhosis and hepatic carcinogenesis. We previously reported that a series of microRNAs (miRNAs) mapped in the 14q32.2 maternally imprinted gene region (Dlk1-Dio3 mat) are related to NAFLD development and progression in a mouse model. We examined the suitability of miR-379, a circulating Dlk1-Dio3 mat miRNA, as a human NAFLD biomarker.MethodsEighty NAFLD patients were recruited for this study. miR-379 was selected from the putative Dlk1-Dio3 mat miRNA cluster because it exhibited the greatest expression difference between NAFLD and non-alcoholic steatohepatitis in our preliminary study. Real-time PCR was used to examine the expression levels of miR-379 and miR-16 as an internal control. One patient was excluded due to low RT-PCR signal.ResultsCompared to normal controls, serum miR-379 expression was significantly up-regulated in NAFLD patients. Receiver operating characteristic curve analysis suggested that miR-379 is a suitable marker for discriminating NAFLD patients from controls, with an area under the curve value of 0.72. Serum miR-379 exhibited positive correlations with alkaline phosphatase, total cholesterol, low-density-lipoprotein cholesterol and non-high-density-lipoprotein cholesterol levels in patients with early stage NAFLD (Brunt fibrosis stage 0 to 1). The correlation between serum miR-379 and cholesterol levels was lost in early stage NAFLD patients treated with statins. Software-based predictions indicated that various energy metabolism-related genes, including insulin-like growth factor-1 (IGF-1) and IGF-1 receptor, are potential targets of miR-379.ConclusionsSerum miR-379 exhibits high potential as a biomarker for NAFLD. miR-379 appears to increase cholesterol lipotoxicity, leading to the development and progression of NAFLD, via interference with the expression of target genes, including those related to the IGF-1 signaling pathway. Our results could facilitate future research into the pathogenesis, diagnosis, and treatment of NAFLD.