Department of Minimally Invasive Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China (mainland).
Department of General Surgery, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China (mainland).
Med Sci Monit. 2019 Apr 23;25:2293-3004. doi: 10.12659/MSM.914044.
BACKGROUND The occurrence of nonalcoholic fatty liver disease (NAFLD) is closely related to type 2 diabetes, especially in patients with insulin resistance. The purpose of this research was to elucidate the major genes and transcriptional regulation of insulin resistance in the progression of NAFLD. MATERIAL AND METHODS We downloaded the gene expression matrix of GSE89632 from Gene Expression Omnibus. Then the principal component analysis was used to identify whether the samples were clustered. Differentially expressed genes were identified by limma R package. Enrichment analysis and protein‑protein interaction network was used to find potential function and screening hub genes. We further used ChIP-seq data from ENCODE to predict the transcriptional regulation of hub genes. Finally, we verified the functions of hub genes with clinical information. RESULTS These hub genes were significantly enriched in "response to insulin", "response to glucose", and "fat cell differentiation". ChIP-seq data showed that EGR1 (early growth response gene-1) may play an important role in the transcriptional regulation of SOCS1 (suppressor of cytokine signaling 1), SOCS3 (suppressor of cytokine signaling 3), and Fos gene family in the liver, as the low expression of EGR1 in patients with insulin resistance may promote the occurrence and development of NAFLD. Similarly, correlation analysis showed that EGR1 was positively correlated with the expression of SOCS1, SOCS3, and the genes of Fos gene family, and EGR1 was negatively correlated with the degree of steatosis. CONCLUSIONS Newly identified hub genes and their transcriptional regulation may promote understanding of the molecular mechanisms underlying insulin resistance related to the progression of NAFLD and provide a new therapy target and biomarkers.
非酒精性脂肪性肝病（NAFLD）的发生与 2 型糖尿病密切相关，尤其是在胰岛素抵抗患者中。本研究旨在阐明胰岛素抵抗在 NAFLD 进展过程中的主要基因和转录调控。
我们从基因表达综合数据库（GEO）中下载了 GSE89632 的基因表达矩阵。然后，我们使用主成分分析来识别样本是否聚类。使用 limma R 包鉴定差异表达基因。通过富集分析和蛋白质-蛋白质相互作用网络寻找潜在的功能和筛选枢纽基因。我们进一步使用 ENCODE 的 ChIP-seq 数据来预测枢纽基因的转录调控。最后，我们结合临床信息验证了枢纽基因的功能。
这些枢纽基因在“对胰岛素的反应”、“对葡萄糖的反应”和“脂肪细胞分化”中显著富集。ChIP-seq 数据显示，早期生长反应基因-1（EGR1）可能在肝脏中 SOCS1（细胞因子信号转导抑制因子 1）、SOCS3（细胞因子信号转导抑制因子 3）和 Fos 基因家族的转录调控中发挥重要作用，因为胰岛素抵抗患者中 EGR1 的低表达可能促进 NAFLD 的发生和发展。同样，相关性分析表明，EGR1 与 SOCS1、SOCS3 和 Fos 基因家族的基因表达呈正相关，与脂肪变性程度呈负相关。
新鉴定的枢纽基因及其转录调控可能有助于理解与 NAFLD 进展相关的胰岛素抵抗的分子机制，并为新的治疗靶点和生物标志物提供依据。
