Integrative microRNA profiling in alcoholic hepatitis reveals a role for microRNA-182 in liver injury and inflammation
Integrative microRNA profiling in alcoholic hepatitis reveals a role for microRNA-182 in liver injury and inflammation
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DOI：
10.1136/gutjnl-2015-311314
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发表时间：
2016-09-01
期刊：
影响因子：
24.5
通讯作者：
Sancho-Bru, Pau
中科院分区：
文献类型：
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作者：
Blaya, Delia;Coll, Mar;Sancho-Bru, Pau
客观microRNA（miRNA）是疾病发病机理的众所周知的调节剂，作为生物标志物和治疗靶标具有很大的潜力。我们旨在分析酒精性肝炎（AH）中的miRNA，并确定可能涉及肝损伤的miRNA。设计miRNA分析是在来自AH，酒精肝病，非酒精性脂肪性肝炎，HCV疾病和正常肝组织的肝脏样品中进行的miRNA分析。在肝脏中评估了miRNA的表达和来自AH和动物模型患者的血清。在体外和体内使用模拟和诱饵miR-182来评估miR-182的生物学功能。肝脏中的miRNA表达谱在AH中高度改变，并且与酒精诱导的肝硬化肝脏不同。此外，与其他慢性肝脏条件相比，我们确定了在AH中主要表达的18个miRNA。综合miRNA-MRNA功能分析揭示了改变AH的miRNA与核受体，IGF-1信号传导和胆汁淤积的关联。有趣的是，miR-182是AH中最高表达的miRNA，它与导管反应，疾病严重程度和短期死亡率相关。 miR-182模拟诱导胆道细胞中炎症介质的上调。在实验水平上，用3,5-二氧基氧基-1,4-二氢核苷（DDC）饮食喂养的小鼠的胆汁细胞中的miR-182增加，但不受酒精摄入或纤维化的上调。在DDC喂养小鼠中抑制miR-182可减少肝脏损伤，胆汁酸的积累和炎症反应。结论性AH的特征是受管制的miRNA特征，包括miR-182，这与疾病的严重程度和肝损伤有关。这些结果突出了miRNA作为AH中治疗靶标和生物标志物的潜力。
Objective MicroRNAs (miRNAs) are well-known regulators of disease pathogenesis and have great potential as biomarkers and therapeutic targets. We aimed at profiling miRNAs in alcoholic hepatitis (AH) and identifying miRNAs potentially involved in liver injury.Design MiRNA profiling was performed in liver samples from patients with AH, alcohol liver disease, nonalcoholic steatohepatitis, HCV disease and normal liver tissue. Expression of miRNAs was assessed in liver and serum from patients with AH and animal models. Mimic and decoy miR-182 were used in vitro and in vivo to evaluate miR-182's biological functions.Results MiRNA expression profile in liver was highly altered in AH and distinctive from alcohol-induced cirrhotic livers. Moreover, we identified a set of 18 miRNAs predominantly expressed in AH as compared with other chronic liver conditions. Integrative miRNA-mRNA functional analysis revealed the association of AH-altered miRNAs with nuclear receptors, IGF-1 signalling and cholestasis. Interestingly, miR-182 was the most highly expressed miRNA in AH, which correlated with degree of ductular reaction, disease severity and short-term mortality. MiR-182 mimic induced an upregulation of inflammatory mediators in biliary cells. At experimental level, miR-182 was increased in biliary cells in mice fed with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet but not upregulated by alcohol intake or fibrosis. Inhibition of miR-182 in DDC-fed mice reduced liver damage, bile acid accumulation and inflammatory response.Conclusions AH is characterised by a deregulated miRNA profile, including miR-182, which is associated with disease severity and liver injury. These results highlight the potential of miRNAs as therapeutic targets and biomarkers in AH.