Hepatic function is preserved in the absence of mature microRNAs.
Hepatic function is preserved in the absence of mature microRNAs.
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DOI：
10.1002/hep.22656
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发表时间：
2009-02
期刊：
影响因子：
13.5
通讯作者：
Friedman, Joshua R.
中科院分区：
文献类型：
--
作者：
Hand, Nicholas J.;Master, Zankhana R.;Le Lay, John;Friedman, Joshua R.
miRNAs是一种非编码的小分子RNA，通过与靶mRNA的部分或完全互补来调节基因表达。miRNAs在正常肝脏生理学中的功能在很大程度上是未知的。在这里，我们解决Dicer 1在分化的肝脏中的作用。我们衍生了肝细胞中缺乏Dicer 1功能的小鼠，并通过定量PCR评估了成熟miRNA的丢失。对来自突变小鼠和对照小鼠的肝RNA进行基因表达微阵列分析。检查突变小鼠和对照小鼠的肝切片，并进行肝功能检查。肝细胞中缺乏Dicer 1功能的小鼠出现并表现正常。尽管成熟miRNAs丢失，肝功能得以维持，如正常血糖、白蛋白、胆固醇和胆红素所反映的。然而，2-4月龄的突变小鼠表现出进行性肝细胞损伤，血清ALT和AST升高。突变小鼠的肝脏质量增加，增殖和凋亡的细胞标志物也增加。微阵列分析表明基因表达发生了大规模的变化，许多miRNA靶点的表达增加，特别是印迹基因。妊娠晚期肝脏中miRNA加工的丧失具有显着轻微的表型，表明miRNA在肝功能中不发挥重要作用。然而，miRNA缺陷导致肝细胞凋亡、肝细胞再生和门静脉炎症。最后，突变体肝脏基因表达的微阵列分析支持了先前假设的Dicer 1在抑制印迹基因中的作用。
MiRNAs are small non-coding RNA molecules that regulate gene expression through partial or complete complementarity with target mRNAs. The function of miRNAs in normal liver physiology is largely unknown. Here we address the role of Dicer1 in the differentiated liver. We derived mice lacking Dicer1 function in hepatocytes and assessed the loss of mature miRNA by quantitative PCR. Gene expression microarray analysis was performed on liver RNA from mutant and control mice. Liver sections from mutant and control mice were examined and liver function tests were performed. Mice lacking Dicer1 function in hepatocytes appeared and behaved normally. Despite the loss of mature miRNAs, hepatic function was maintained, as reflected by normal blood glucose, albumin, cholesterol, and bilirubin. However, mutant mice between 2-4 months of age exhibited progressive hepatocyte damage with elevated serum ALT and AST. Liver mass was increased in mutant mice, as were cellular markers of both proliferation and apoptosis. Microarray analysis indicated large-scale changes in gene expression, with increased expression of many miRNA targets, particularly imprinted genes. Loss of miRNA processing in the liver at late gestation has a remarkably mild phenotype, suggesting that miRNAs do not play an essential role in hepatic function. However, miRNA deficiency results in hepatocyte apoptosis, hepatocyte regeneration, and portal inflammation. Finally, microarray analysis of gene expression in mutant liver supports a previously hypothesized role for Dicer1 in the repression of imprinted genes.
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