Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa, Japan.
PLoS One. 2012;7(2):e30250. doi: 10.1371/journal.pone.0030250. Epub 2012 Feb 17.
MicroRNAs (miRNAs) are small RNA molecules that function to modulate the expression of target genes, playing important roles in a wide range of physiological and pathological processes. The miRNAs in body fluids have received considerable attention as potential biomarkers of various diseases. In this study, we compared the changes of the plasma miRNA expressions by acute liver injury (hepatocellular injury or cholestasis) and chronic liver injury (steatosis, steatohepatitis and fibrosis) using rat models made by the administration of chemicals or special diets. Using miRNA array analysis, we found that the levels of a large number of miRNAs (121-317 miRNAs) were increased over 2-fold and the levels of a small number of miRNAs (6-35 miRNAs) were decreased below 0.5-fold in all models except in a model of cholestasis caused by bile duct ligation. Interestingly, the expression profiles were different between the models, and the hierarchical clustering analysis discriminated between the acute and chronic liver injuries. In addition, miRNAs whose expressions were typically changed in each type of liver injury could be specified. It is notable that, in acute liver injury models, the plasma level of miR-122, the most abundant miRNA in the liver, was more quickly and dramatically increased than the plasma aminotransferase level, reflecting the extent of hepatocellular injury. This study demonstrated that the plasma miRNA profiles could reflect the types of liver injury (e.g. acute/chronic liver injury or hepatocellular injury/cholestasis/steatosis/steatohepatitis/fibrosis) and identified the miRNAs that could be specific and sensitive biomarkers of liver injury.
微小 RNA(miRNA)是一种小 RNA 分子,可调节靶基因的表达,在广泛的生理和病理过程中发挥重要作用。体液中的 miRNA 作为各种疾病的潜在生物标志物受到了相当多的关注。在这项研究中,我们通过化学物质或特殊饮食给药的大鼠模型,比较了急性肝损伤(肝细胞损伤或胆汁淤积)和慢性肝损伤(脂肪变性、脂肪性肝炎和纤维化)时血浆 miRNA 表达的变化。使用 miRNA 阵列分析,我们发现除胆管结扎引起的胆汁淤积模型外,所有模型中大量 miRNA(121-317 个 miRNA)的水平增加了 2 倍以上,少数 miRNA(6-35 个 miRNA)的水平降低了 0.5 倍以下。有趣的是,这些模型之间的表达谱不同,层次聚类分析可区分急性和慢性肝损伤。此外,还可以确定每种类型肝损伤中表达通常发生变化的 miRNA。值得注意的是,在急性肝损伤模型中,肝脏中含量最丰富的 miRNA miR-122 的血浆水平比血浆转氨酶水平更快、更显著地升高,反映了肝细胞损伤的程度。本研究表明,血浆 miRNA 谱可以反映肝损伤的类型(如急性/慢性肝损伤或肝细胞损伤/胆汁淤积/脂肪变性/脂肪性肝炎/纤维化),并鉴定出可能是肝损伤特异性和敏感生物标志物的 miRNA。