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首页> 外文期刊>Translational research: the journal of laboratory and clinical medicine >High-throughput sequencing reveals altered expression of hepatic microRNAs in nonalcoholic fatty liver disease-related fibrosis
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High-throughput sequencing reveals altered expression of hepatic microRNAs in nonalcoholic fatty liver disease-related fibrosis

机译：高通量测序显示在非酒精性脂肪肝疾病相关纤维化中的肝脏微小RORNA的改变表达

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Recent evidence suggests that microRNAs (miRNAs), small, noncoding RNA molecules that regulate gene expression, may play a role in the regulation of metabolic disorders, including nonalcoholic fatty liver disease (NAFLD). To identify miRNAs that mediate NAFLD-related fibrosis, we used high-throughput sequencing to assess miRNAs obtained from liver biopsies of 15 individuals without NAFLD fibrosis (F0) and 15 individuals with severe NAFLD fibrosis or cirrhosis (F3-F4), matched for age, sex, body mass index, type 2 diabetes status, hemoglobin Alc, and use of diabetes medications. We used DESeq2 and Kruskal-Wallis test to identify miRNAs that were differentially expressed between NAFLD patients with or without fibrosis, adjusting for multiple testing using Bonferroni correction. We identified a total of 75 miRNAs showing statistically significant evidence (adjusted P value 0.05) for differential expression between the 2 groups, including 30 upregulated and 45 downregulated miRNAs. Quantitative reverse-transcription polymerase chain reaction analysis of selected miRNAs identified by sequencing validated 9 of 11 of the top differentially expressed miRNAs. We performed functional enrichment analysis of dysregulated miRNAs and identified several potential gene targets related to NAFLD-related fibrosis including hepatic fibrosis, hepatic stellate cell activation, transforming growth factor beta signaling, and apoptosis signaling. We identified forkhead box 03 and F-box WD repeat domain containing 7, E3 ubiquitin protein ligase (FBXW7) as potential targets of miR-182, and found that levels of forkhead box 03, but not FBXW7, were significantly decreased in fibrotic samples. These findings support a role for hepatic miRNAs in the pathogenesis of NAFLD-related fibrosis and yield possible new insight into the molecular mechanisms underlying the initiation and progression of liver fibrosis and cirrhosis.
机译：最近的证据表明，调节基因表达的微小RNA（miRNA），小，非编码的RNA分子可能在调节代谢紊乱的调节中起作用，包括非酒精性脂肪肝病（NAFLD）。为了鉴定介导NAFLD相关纤维化的miRNA，我们使用高通量测序来评估从15个个体的肝活组织检查获得的miRNA，没有NAFLD纤维化（F0）和15个具有严重NAFLD纤维化或肝硬化（F3-F4）的15个个体，符合年龄，性别，体重指数，2型糖尿病状态，血红蛋白ALC，以及糖尿病药物的使用。我们使用Deseq2和Kruskal-Wallis测试来鉴定米兰德患者在有或没有纤维化的NAFLD患者之间表达的miRNA，用于使用Bonferroni校正调整多次测试。我们鉴定了总共75个miRNA，显示出统计上有明显的证据（调节的p值<0.05），用于2组之间的差异表达，包括30个上调和45个下调的miRNA。通过测序验证的验证的鉴定的鉴定的近摄差异11的差异表达的miRNA中的验证的定量逆转录聚合酶链反应分析。我们对癫痫测定MiRNA进行了功能性富集分析，并确定了与NAFLD相关纤维化相关的几个潜在基因靶标，包括肝纤维化，肝星状细胞活化，转化生长因子β信号传导和凋亡信号传导。我们识别出含有7，E3泛素蛋白连接酶（FBXW7）的FORKHEAD框03和F箱WD重复域作为miR-182的潜在靶标，发现纤维化样品中的叉头框03的水平但不是FBXW7。这些发现支持肝miRNA在NAFLD相关纤维化的发病机制中的作用，并且可以对肝纤维化和肝硬化引发和进展的分子机制产生新的洞察力。

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