Lou Yi, Chen Yi-Dan, Sun Fu-Rong, Shi Jun-Ping, Song Yu, Yang Jin
Cell Physiol Biochem. 2017;41(1):239-251. doi: 10.1159/000456061. Epub 2017 Jan 30.
The incidence of nonalcoholic fatty liver disease (NAFLD), ranging from mild steatosis to hepatocellular injury and inflammation, increases with the rise of obesity. However, the implications of transcription factors network in progressive NAFLD remain to be determined.
A co-regulatory network approach by combining gene expression and transcription influence was utilized to dissect transcriptional regulators in different NAFLD stages. In vivo, mice models of NAFLD were used to investigate whether dysregulated expression be undertaken by transcriptional regulators.
Through constructing a large-scale co-regulatory network, sample-specific regulator activity was estimated. The combinations of active regulators that drive the progression of NAFLD were identified. Next, top regulators in each stage of NAFLD were determined, and the results were validated using the different experiments and bariatric surgical samples. In particular, Adipocyte enhancer-binding protein 1 (AEBP1) showed increased transcription activity in nonalcoholic steatohepatitis (NASH). Further characterization of the AEBP1 related transcription program defined its co-regulators, targeted genes, and functional organization. The dynamics of AEBP1 and its potential targets were verified in an animal model of NAFLD.
This study identifies putative functions for several transcription factors in the pathogenesis of NAFLD and may thus point to potential targets for therapeutic interventions.
非酒精性脂肪性肝病（NAFLD）的发病率随肥胖率上升而增加，其病变范围从轻度脂肪变性到肝细胞损伤及炎症。然而，转录因子网络在进展性NAFLD中的作用仍有待确定。
采用结合基因表达和转录影响的共调控网络方法，剖析不同NAFLD阶段的转录调节因子。在体内，利用NAFLD小鼠模型研究转录调节因子是否会导致表达失调。
通过构建大规模共调控网络，估计了样本特异性调节因子活性。确定了驱动NAFLD进展的活性调节因子组合。接下来，确定了NAFLD各阶段的顶级调节因子，并使用不同实验和减肥手术样本对结果进行了验证。特别是，脂肪细胞增强子结合蛋白1（AEBP1）在非酒精性脂肪性肝炎（NASH）中显示出转录活性增加。对AEBP1相关转录程序的进一步表征确定了其共调节因子、靶基因和功能组织。在NAFLD动物模型中验证了AEBP1及其潜在靶点的动态变化。
本研究确定了几种转录因子在NAFLD发病机制中的推定功能，因此可能指出治疗干预的潜在靶点。
