Pirola Carlos J, Fernández Gianotti Tomas, Castaño Gustavo O, Mallardi Pablo, San Martino Julio, Mora Gonzalez Lopez Ledesma María, Flichman Diego, Mirshahi Faridodin, Sanyal Arun J, Sookoian Silvia
Department of Molecular Genetics and Biology of Complex Diseases, Institute of Medical Research A Lanari-IDIM, University of Buenos Aires-National Scientific and Technical Research Council (CONICET), Ciudad Autónoma de Buenos Aires, Argentina.
Liver Unit, Medicine and Surgery Department, Hospital Abel Zubizarreta, Ciudad Autónoma de Buenos Aires, Argentina.
Gut. 2015 May;64(5):800-12. doi: 10.1136/gutjnl-2014-306996. Epub 2014 Jun 27.
We used a screening strategy of global serum microRNA (miRNA) profiling, followed by a second stage of independent replication and exploration of liver expression of selected miRNAs to study: (1) the circulating miRNA signature associated with non-alcoholic fatty liver disease (NAFLD) progression and predictive power, (2) the role of miRNAs in disease biology and (3) the association between circulating miRNAs and features of the metabolic syndrome.
The study used a case-control design and included patients with NAFLD proven through biopsy and healthy controls.
Among 84 circulating miRNAs analysed, miR-122, miR-192, miR-19a and miR-19b, miR-125b, and miR-375 were upregulated >2-fold (p<0.05) either in simple steatosis (SS) or non-alcoholic steatohepatitis (NASH). The most dramatic and significant fold changes were observed in the serum levels of miR-122 (7.2-fold change in NASH vs controls and 3.1-fold change in NASH vs SS) and miR-192 (4.4-fold change in NASH vs controls); these results were replicated in the validation set. The majority of serum miR-122 circulate in argonaute2-free forms. Circulating miR-19a/b and miR-125b were correlated with biomarkers of atherosclerosis. Liver miR-122 expression was 10-fold (p<0.03) downregulated in NASH compared with SS and was preferentially expressed at the edge of lipid-laden hepatocytes. In vitro exploration showed that overexpression of miR-122 enhances alanine aminotransferase activity.
miR-122 plays a role of physiological significance in the biology of NAFLD; circulating miRNAs mirror the histological and molecular events occurring in the liver. NAFLD has a distinguishing circulating miRNA profile associated with a global dysmetabolic disease state and cardiovascular risk.
我们采用了一种全球血清微小RNA（miRNA）谱筛查策略，随后进行第二阶段的独立复制和所选miRNA肝脏表达的探索，以研究：（1）与非酒精性脂肪性肝病（NAFLD）进展相关的循环miRNA特征及其预测能力；（2）miRNA在疾病生物学中的作用；（3）循环miRNA与代谢综合征特征之间的关联。
本研究采用病例对照设计，纳入经活检证实的NAFLD患者和健康对照。
在分析的84种循环miRNA中，miR-122、miR-192、miR-19a和miR-19b、miR-125b以及miR-375在单纯性脂肪肝（SS）或非酒精性脂肪性肝炎（NASH）中上调超过2倍（p<0.05）。在miR-122（NASH与对照相比变化7.2倍，NASH与SS相比变化3.1倍）和miR-192（NASH与对照相比变化4.4倍）的血清水平中观察到最显著的倍数变化；这些结果在验证集中得到了重复。大多数血清miR-122以无AGO2的形式循环。循环miR-19a/b和miR-125b与动脉粥样硬化生物标志物相关。与SS相比，NASH中肝脏miR-122表达下调10倍（p<0.03），且在充满脂质的肝细胞边缘优先表达。体外探索表明，miR-122的过表达增强了丙氨酸转氨酶活性。
miR-122在NAFLD生物学中发挥着具有生理意义的作用；循环miRNA反映了肝脏中发生的组织学和分子事件。NAFLD具有与整体代谢紊乱疾病状态和心血管风险相关的独特循环miRNA谱。
