Mahmoudi Ali, Butler Alexandra E, Orekhov Alexander N, Jamialahmadi Tannaz, Sahebkar Amirhossein
Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
Department of Medical Biotechnology and Nanotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
Curr Med Chem. 2025;32(7):1355-1377. doi: 10.2174/0929867331666230829164832.
The hallmark of non-alcoholic fatty liver disease (NAFLD) is aberrant buildup of triglycerides (TGs) in hepatocytes. Many genes promote NAFLD development. Using bioinformatics tools, we investigated the possible effect of statins on genes involved in NAFLD progression.
Protein interactions of statins and NAFLD were searched in gene-drug and gene-disease databases. A Protein-Protein interaction (PPI) network was constructed to find hub genes and Molecular Complex Detection (MCODE) of NAFLD-related genes. Shared protein targets between protein targets of statins and NAFLD-associated genes were identified. Next, targets of each statin were assayed with all modular clusters in the MCODEs related to NAFLD. Biological process and pathway enrichment analysis for shared proteins was performed.
Screening protein targets for conventional statins and curated NAFLD-related genes identified 343 protein targets and 70 genes, respectively. A Venn diagram of NAFLD-related genes and protein targets of statins showed 24 shared proteins. The biological pathways on KEGG enrichment associated with the 24 shared protein sets were evaluated and included cytokine-cytokine receptor interaction, adipocytokine, PPAR, TNF and AMPK signaling pathways. Gene Ontology analysis showed major involvement in lipid metabolic process regulation and inflammatory response. PPI network analysis of 70 protein targets indicated 13 hub genes (PPARA, IL4, CAT, LEP, SREBF1, PRKCA, CYP2E1, NFE2L2, PTEN, NR1H4, ADIPOQ, GSTP1 and TGFB1). Comparing all seven statins with the three MCODE clusterings and 13 hub genes revealed that simvastatin as the most associated statin with NAFLD.
Simvastatin has the most impact on NAFLD-related genes versus other statins.
非酒精性脂肪性肝病（NAFLD）的标志是肝细胞内甘油三酯（TGs）异常蓄积。许多基因促进NAFLD的发展。我们使用生物信息学工具研究了他汀类药物对参与NAFLD进展的基因的可能影响。
在基因-药物和基因-疾病数据库中搜索他汀类药物与NAFLD的蛋白质相互作用。构建蛋白质-蛋白质相互作用（PPI）网络以找到枢纽基因和NAFLD相关基因的分子复合物检测（MCODE）。确定他汀类药物的蛋白质靶点与NAFLD相关基因之间的共享蛋白质靶点。接下来，用与NAFLD相关的MCODE中的所有模块簇分析每种他汀类药物的靶点。对共享蛋白质进行生物学过程和通路富集分析。
筛选传统他汀类药物的蛋白质靶点和精心整理的NAFLD相关基因，分别鉴定出343个蛋白质靶点和70个基因。NAFLD相关基因与他汀类药物蛋白质靶点的维恩图显示有24种共享蛋白质。评估了与这24种共享蛋白质集相关的KEGG富集的生物学通路，包括细胞因子-细胞因子受体相互作用、脂肪细胞因子、PPAR、TNF和AMPK信号通路。基因本体分析表明主要参与脂质代谢过程调节和炎症反应。对70个蛋白质靶点的PPI网络分析表明有13个枢纽基因（PPARA、IL4、CAT、LEP、SREBF1、PRKCA、CYP2E1、NFE2L2、PTEN、NR1H4、ADIPOQ、GSTP1和TGFB1）。将所有七种他汀类药物与三个MCODE聚类和13个枢纽基因进行比较，发现辛伐他汀是与NAFLD最相关的他汀类药物。
与其他他汀类药物相比，辛伐他汀对NAFLD相关基因的影响最大。
