Chen Xiyu, Deng Shi-Zhou, Sun Yuze, Bai Yunhu, Wang Yayun, Yang Yanling
Department of Hepatobiliary Surgery, Xi-Jing Hospital, The Fourth Military Medical University, Xi'an, China.
Department of General Surgery, 988 Hospital of Joint Logistic Support Force, Zhengzhou, China.
Front Endocrinol (Lausanne). 2024 Feb 26;15:1338889. doi: 10.3389/fendo.2024.1338889. eCollection 2024.
Nonalcoholic steatohepatitis (NASH) is the advanced stage of nonalcoholic fatty liver disease (NAFLD), one of the most prevalent chronic liver diseases. The effectiveness of bariatric surgery in treating NASH and preventing or even reversing liver fibrosis has been demonstrated in numerous clinical studies, but the underlying mechanisms and crucial variables remain unknown.
Using the GSE135251 dataset, we examined the gene expression levels of NASH and healthy livers. Then, the differentially expressed genes (DEGs) of patients with NASH, at baseline and one year after bariatric surgery, were identified in GSE83452. We overlapped the hub genes performed by protein-protein interaction (PPI) networks and DEGs with different expression trends in both datasets to obtain key genes. Genomic enrichment analysis (GSEA) and genomic variation analysis (GSVA) were performed to search for signaling pathways of key genes. Meanwhile, key molecules that regulate the key genes are found through the construction of the ceRNA network. NASH mice were induced by a high-fat diet (HFD) and underwent sleeve gastrectomy (SG). We then cross-linked the DEGs in clinical and animal samples using quantitative polymerase chain reaction (qPCR) and validated the key genes.
Seven key genes (FASN, SCD, CD68, HMGCS1, SQLE, CXCL10, IGF1) with different expression trends in GSE135251 and GSE83452 were obtained with the top 30 hub genes selected by PPI. The expression of seven key genes in mice after SG was validated by qPCR. Combined with the qPCR results from NASH mice, the four genes FASN, SCD, HMGCS1, and CXCL10 are consistent with the biological analysis. The GSEA results showed that the 'cholesterol homeostasis' pathway was enriched in the FASN, SCD, HMGCS1, and SQLE high-expression groups. The high-expression groups of CD68 and CXCL10 were extremely enriched in inflammation-related pathways. The construction of the ceRNA network obtained microRNAs and ceRNAs that can regulate seven key genes expression.
In summary, this study contributes to our understanding of the mechanisms by which bariatric surgery improves NASH, and to the development of potential biomarkers for the treatment of NASH.
非酒精性脂肪性肝炎（NASH）是非酒精性脂肪性肝病（NAFLD）的晚期阶段，NAFLD是最常见的慢性肝病之一。减肥手术在治疗NASH以及预防甚至逆转肝纤维化方面的有效性已在众多临床研究中得到证实，但其潜在机制和关键变量仍不清楚。
使用GSE135251数据集，我们检测了NASH患者和健康肝脏的基因表达水平。然后，在GSE83452中确定了NASH患者在基线时以及减肥手术后一年的差异表达基因（DEG）。我们将蛋白质-蛋白质相互作用（PPI）网络筛选出的前30个枢纽基因与两个数据集中具有不同表达趋势的DEG进行重叠，以获得关键基因。进行基因组富集分析（GSEA）和基因组变异分析（GSVA）以寻找关键基因的信号通路。同时，通过构建ceRNA网络找到调控关键基因的关键分子。用高脂饮食（HFD）诱导NASH小鼠并进行袖状胃切除术（SG）。然后，我们使用定量聚合酶链反应（qPCR）对临床和动物样本中的DEG进行交叉验证，并验证关键基因。
通过PPI筛选出的前30个枢纽基因，我们在GSE135251和GSE83452中获得了7个具有不同表达趋势的关键基因（FASN、SCD、CD68、HMGCS1、SQLE、CXCL10、IGF1）。通过qPCR验证了SG术后小鼠中7个关键基因的表达。结合NASH小鼠的qPCR结果，FASN、SCD、HMGCS1和CXCL10这四个基因与生物学分析结果一致。GSEA结果显示，“胆固醇稳态”途径在FASN、SCD、HMGCS1和SQLE高表达组中富集。CD68和CXCL10的高表达组在炎症相关途径中极度富集。ceRNA网络的构建获得了可调控7个关键基因表达的微小RNA和ceRNA。
总之，本研究有助于我们理解减肥手术改善NASH的机制，并有助于开发治疗NASH的潜在生物标志物。
