Gene expression in the liver of ethanol-treated mice via gastric tube in multiple strains. Mus musculus

This study tested a hypothesis that a population-based approach may identify genetic background-dependent and -independent genes/pathways that modulate alcohol-induced liver injury. A sub-chronic (4 weeks) intra-gastric alcohol infusion (up to 27 g/kg/day) model was used to control for alcohol intake in 15 genetically diverse inbred mouse strains. Urine, serum and liver markers of alcoholic steato-hepatitis were assessed and a wide range of liver damage was observed across the panel. Gene expression profiling was performed on liver tissue collected at the end of the study and statistical models, with strain, degree of liver injury, treatment, and their interaction terms as factors, were used to select transcripts associated with strain-dependent and -independent effects of alcohol on the liver. Translational control of hepatic protein synthesis, related to eukaryotic initiation factors (eiFs) and accessory proteins, was identified as genetic background-independent mode of alcohol-induced liver injury. Interestingly, immune response-related transcription factors signal transducer and activator of transcription 1 (Stat1) and nuclear factor, interleukin 3 regulated (Nfil3/E4bp4) are likely determinants of genetic background-dependent responses to liver injury and alcohol treatment, respectively. Our data demonstrate that a multistrain approach provides critical mechanistic information for understanding genetic factors influencing alcohol toxicity and facilitate identification of novel targets of therapeutic intervention. Overall design: A high-fat diet or EtOH-containing high-fat diet was administered to 15 strains of mice via gastric tube for 28 days. 3 replicates per strain/diet. Inter-batch normalization was carried out using the ComBat procedure. The supplementary file 'GSE20052_Readme.txt' contains a description of the replicates used for normalization. The 'GSE20052_US14702406_25148681*' files linked to the GSE20052 record are the raw data files for the replicates.

本研究验证了如下假说：基于群体的研究方法可识别出调控酒精诱导肝损伤的、依赖于遗传背景与不依赖于遗传背景的基因及通路。本研究采用亚慢性（4周）经胃酒精灌注模型（最高剂量达27 g/kg/天），对15种遗传多样性近交系小鼠的酒精摄入量进行精准控制。研究人员对酒精性脂肪性肝炎的尿液、血清及肝脏标志物进行检测，结果显示该小鼠队列中存在广泛程度的肝损伤差异。于实验结束时收集肝脏组织开展基因表达谱分析，并以小鼠品系、肝损伤程度、酒精处理及其交互项作为因素构建统计模型，筛选出与酒精对肝脏作用的品系依赖与非依赖效应相关的转录本。研究发现，与真核起始因子（eukaryotic initiation factors, eiFs）及辅助蛋白相关的肝脏蛋白质合成翻译调控通路，是酒精诱导肝损伤的遗传背景非依赖调控模式。值得注意的是，免疫应答相关转录因子信号转导与转录激活因子1（signal transducer and activator of transcription 1, Stat1）以及核因子白细胞介素3调控蛋白（nuclear factor, interleukin 3 regulated, Nfil3/E4bp4），分别可能是遗传背景依赖的肝损伤应答与酒精处理应答的关键决定因素。本研究数据表明，多品系研究方法可为解析影响酒精毒性的遗传因素提供关键机制信息，并助力识别新型治疗干预靶点。实验设计概述：通过胃管向15种小鼠品系饲喂高脂饮食或含酒精的高脂饮食，持续28天。每个品系/饮食组合设置3个生物学重复。采用ComBat程序进行批次间标准化处理。补充文件'GSE20052_Readme.txt'中包含了用于标准化处理的重复样本说明。与GSE20052记录关联的'GSE20052_US14702406_25148681*'文件为对应重复样本的原始数据文件。