Wang Wen, Liu Xiaojing, Wei Peiyao, Ye Feng, Chen Yunru, Shi Lei, Zhang Xi, Li Jianzhou, Lin Shumei, Yang Xueliang
Department of Infectious Diseases, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
Department of Nutrition, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
Front Med (Lausanne). 2022 Apr 19;9:862278. doi: 10.3389/fmed.2022.862278. eCollection 2022.
Non-alcoholic fatty liver disease (NAFLD) is a major chronic liver disease worldwide, and non-alcoholic steatohepatitis (NASH) is one of its pathological subtypes. The pathogenesis of NASH has not yet been fully elucidated. The purpose of this study was to identify the hub genes and pathways involved in NASH using bioinformatics methods. The hub genes were confirmed in human and animal models.
Three Gene Expression Omnibus (GEO) datasets (GSE48452, GSE58979, and GSE151158) of NASH patients and healthy controls were included in the study. We used GEO2R to identify differentially expressed genes (DEGs) between NASH patients and healthy controls. Functional enrichment analyses were then performed to explore the potential functions and pathways of the DEGs. In all DEGs, only two genes were highly expressed in NASH patients throughout the three datasets; these two genes, and , were further studied. Serum and liver tissues from NASH patients and healthy controls were collected. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were measured in NASH patients and healthy controls. Liver tissues were stained with hematoxylin and eosin. Immunohistochemical staining was used to evaluate the expression levels of the two genes in liver tissues. Male C57BL/6J mice were fed a methionine choline-deficient (MCD) diet for 8 weeks, after which serum ALT and AST levels were measured and liver tissues were stained.
and were the hub genes detected in the three datasets. "Lipid metabolism," "inflammatory response," and "lymphocyte activation" were the most significant biological functions in GSE48452, GSE58979, and GSE151158, respectively. Kyoto Encyclopedia of Genes and Genomes pathway analysis showed that the toll-like receptor signaling pathway was significantly enriched in NASH patients. Serum ALT and AST levels were significantly increased in NASH patients compared to healthy controls. Liver tissues had more serious steatosis, hepatocyte ballooning degeneration, and lobular inflammatory infiltration, and the expression of and in liver cells was significantly upregulated in NASH patients compared to healthy controls. MCD diet mice were consistent with NASH patients.
and may play important roles in NASH pathogenesis and could be potential therapeutic targets and biomarkers of NASH in the future. Further experimental studies are needed to confirm our results.
非酒精性脂肪性肝病（NAFLD）是全球主要的慢性肝病，非酒精性脂肪性肝炎（NASH）是其病理亚型之一。NASH的发病机制尚未完全阐明。本研究旨在利用生物信息学方法鉴定参与NASH的关键基因和通路。在人类和动物模型中对关键基因进行了验证。
本研究纳入了三个非酒精性脂肪性肝炎患者和健康对照的基因表达综合数据库（GEO）数据集（GSE48452、GSE58979和GSE151158）。我们使用GEO2R来鉴定非酒精性脂肪性肝炎患者和健康对照之间的差异表达基因（DEG）。然后进行功能富集分析，以探索差异表达基因的潜在功能和通路。在所有差异表达基因中，在三个数据集中只有两个基因在非酒精性脂肪性肝炎患者中高表达；对这两个基因进行了进一步研究。收集非酒精性脂肪性肝炎患者和健康对照的血清和肝组织。检测非酒精性脂肪性肝炎患者和健康对照的血清丙氨酸氨基转移酶（ALT）和天冬氨酸氨基转移酶（AST）水平。肝组织用苏木精和伊红染色。采用免疫组织化学染色法评估肝组织中这两个基因的表达水平。雄性C57BL/6J小鼠喂食蛋氨酸胆碱缺乏（MCD）饮食8周，之后检测血清ALT和AST水平并对肝组织进行染色。
和是在三个数据集中检测到的关键基因。“脂质代谢”“炎症反应”和“淋巴细胞活化”分别是GSE48452、GSE58979和GSE151158中最显著的生物学功能。京都基因与基因组百科全书通路分析表明，Toll样受体信号通路在非酒精性脂肪性肝炎患者中显著富集。与健康对照相比，非酒精性脂肪性肝炎患者的血清ALT和AST水平显著升高。肝组织有更严重的脂肪变性、肝细胞气球样变性和小叶炎症浸润，与健康对照相比，非酒精性脂肪性肝炎患者肝细胞中和的表达显著上调。MCD饮食小鼠的情况与非酒精性脂肪性肝炎患者一致。
和可能在非酒精性脂肪性肝炎发病机制中起重要作用，未来可能成为非酒精性脂肪性肝炎的潜在治疗靶点和生物标志物。需要进一步的实验研究来证实我们的结果。
