A role for mammalian target of rapamycin (mTOR) pathway in non alcoholic steatohepatitis related-cirrhosis
A role for mammalian target of rapamycin (mTOR) pathway in non alcoholic steatohepatitis related-cirrhosis
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DOI：
10.14670/hh-25.1123
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发表时间：
2010-09-01
影响因子：
2
通讯作者：
Carneiro D'Albuquerque, Luiz Augusto
中科院分区：
文献类型：
--
作者：
Kubrusly, Marcia Saldanha;Correa-Giannella, Maria Lucia;Carneiro D'Albuquerque, Luiz Augusto
非酒精性脂肪性肝病（NAFLD）包括脂肪变性、非酒精性脂肪性肝炎（NASH）和NASH相关肝硬化（NASH/Cir）的整个谱。虽然在这一领域已经取得了分子进展，但NAFLD的发病机制尚未完全了解。评估了与NASH/Cir相关的基因表达谱，试图更好地表征其发病机制中涉及的途径。研究方法：在第一步中，我们使用cDNA微阵列通过GeneSifter（TM）分析评估正常肝脏（n=3）和NASH/Cir样品（n=3）中的基因表达谱，以鉴定差异表达的基因和生物学途径。第二，使用组织芯片检测11例正常肝脏样本、10例NASH/Cir样本和37例其他病因的肝硬化样本中磷酸化mTOR和4 E-BP 1的免疫组织化学表达，以进一步探索通过基因表达分析证明的mTOR通路的参与。结果：NASH/Cir中有138个基因表达上调，106个基因表达下调。在被鉴定为在NASH/Cir中显著调节的9种途径中，证实了mTOR途径的参与，因为与其他病因的肝硬化和正常肝脏相比，NASH/Cir中细胞质和膜磷酸mTOR的表达更高。结论：最近的研究结果表明细胞“营养传感器”mTOR在NAFLD中的作用，并且本研究证实了该途径在NASH/Cir中的参与。磷酸化mTOR评估可能具有临床实用性，可作为由于缺乏临床数据而被错误认为是隐源性肝硬化的病例中鉴定NASH/Cir的潜在标志物。
Non-alcoholic fatty liver disease (NAFLD) encompasses the whole spectrum of steatosis, nonalcoholic steatohepatitis (NASH), and NASH-related cirrhosis (NASH/Cir). Although molecular advances have been made in this field, the pathogenesis of NAFLD is not completely understood. The gene expression profiling associated to NASH/Cir was assessed, in an attempt to better characterize the pathways involved in its etiopathogenesis. Methods: In the first step, we used cDNA microarray to evaluate the gene expression profiles in normal liver (n=3) and NASH/Cir samples (n=3) by GeneSifter (TM) analysis to identify differentially expressed genes and biological pathways. Second, tissue microarray was used to determine immunohistochemical expression of phosphorylated mTOR and 4E-BP1 in 11 normal liver samples, 10 NASH/Cir samples and in 37 samples of cirrhosis of other etiologies to further explore the involvement of the mTOR pathway evidenced by the gene expression analysis. Results: 138 and 106 genes were, respectively, up and down regulated in NASH/Cir in comparison to normal liver. Among the 9 pathways identified as significantly modulated in NASH/Cir, the participation of the mTOR pathway was confirmed, since expression of cytoplasmic and membrane phospho-mTOR were higher in NASH/Cir in comparison to cirrhosis of other etiologies and to normal liver. Conclusions: Recent findings have suggested a role for the cellular "nutrient sensor" mTOR in NAFLD and the present study corroborates the participation of this pathway in NASH/Cir. Phospho-mTOR evaluation might be of clinical utility as a potential marker for identification of NASH/Cir in cases mistakenly considered as cryptogenic cirrhosis owing to paucity of clinical data.