基于网络药理学探讨GLP-1RAs治疗非酒精性脂肪肝合并糖尿病的作用机制
Exploring the Mechanism of Action of GLP-1RAs in the Treatment of Non-Alcoholic Fatty Liver Disease Combined with Diabetes Based on Network Pharmacology
摘要: 目的：基于网络药理学探讨GLP-1RAs治疗非酒精性脂肪肝合并糖尿病的作用机制。方法：通过Pharmmapper、TargetNET、SEA和the Binding Database数据库查找筛选4种GLP-1RAs的作用靶点。通过GeneCards、DisGeNET以及OMIM查找并筛选NAFLD和T2DM的致病基因。使用DAVID数据库进行GO和KEGG富集分析，Cytoscape3.10.0绘制GLP-1RAs治疗NAFLD和T2DM的“药物–靶点–疾病的网络关系图”，利用MCODE插件进行聚类分析，Hubba插件筛选核心靶点，并绘制“核心靶点–通路的网络图”。结果：通过网络药理学筛选出GLP-1RAs治疗NAFLD合并T2DM的35个潜在靶点，筛选后获得13个核心靶点，它们分别是CASP3、ESR1、SIRT1、IGF1R、CCND1、GSK3B、AR、PRKACA、PARP1、NOS3、REN、MAPK8、ACE1。GO和KEGG富集分析结果表明，RAS系统相关通路和胰岛素抵抗相关通路是研究的关键通路。结论：GLP-1RAs有可能是通过激活RAS系统中ACE2/Ang(1-7)/Mas轴，对抗ACE/AngII/AT1R轴发挥其作用，以及根据血糖水平调节胰岛素的释放，增加胰岛素的生物合成和分泌等途径改善胰岛素抵抗对NAFLD和T2DM表现出有益疗效。
Abstract: Objective: To explore the mechanism of GLP-1RAs in the treatment of non-alcoholic fatty liver disease (NAFLD) complicated with type 2 diabetes mellitus (T2DM) through network pharmacology. Methods: The target proteins of four GLP-1RAs were screened via Pharmmapper, TargetNET, SEA and the Binding Database. The pathogenic genes of NAFLD and T2DM were retrieved and filtered through GeneCards, DisGeNET and OMIM. The DAVID database was employed for GO and KEGG enrichment analysis. Cytoscape3.10.0 was utilized to construct the “drug-target-disease network relationship diagram” for GLP-1RAs in treating NAFLD and T2DM. The MCODE plugin was used for cluster analysis, and the Hubba plugin was applied to screen core targets and create the “core target-pathway network diagram”. Results: Using network pharmacology, we identified 35 potential targets of GLP-1RAs for treating NAFLD with T2DM, and further screening yielded 13 core targets: CASP3, ESR1, SIRT1, IGF1R, CCND1, GSK3B, AR, PRKACA, PARP1, NOS3, REN, MAPK8, and ACE1. GO and KEGG enrichment analysis results indicate that pathways related to the RAS system and insulin resistance are critical pathways in the study. Conclusion: GLP-1RAs may exert their effects by activating the ACE2/Ang(1-7)/Mas axis in the RAS system to counteract the ACE/AngII/AT1R axis, and by regulating insulin release according to blood glucose levels, increasing insulin biosynthesis and secretion, and other pathways to improve insulin resistance, thereby showing beneficial effects on NAFLD and T2DM.
文章引用：齐高林, 张紫祺, 孙佳旭, 张成, 李红艳. 基于网络药理学探讨GLP-1RAs治疗非酒精性脂肪肝合并糖尿病的作用机制[J]. 医学诊断, 2025, 15(2): 200-210. https://doi.org/10.12677/md.2025.152027

参考文献

[1] Pang, Y., Kartsonaki, C., Turnbull, I., Guo, Y., Clarke, R., Chen, Y., et al. (2018) Diabetes, Plasma Glucose, and Incidence of Fatty Liver, Cirrhosis, and Liver Cancer: A Prospective Study of 0.5 Million People. Hepatology, 68, 1308-1318. [Google Scholar] [CrossRef] [PubMed]
[2] Younossi, Z.M., Golabi, P., de Avila, L., Paik, J.M., Srishord, M., Fukui, N., et al. (2019) The Global Epidemiology of NAFLD and NASH in Patients with Type 2 Diabetes: A Systematic Review and Meta-Analysis. Journal of Hepatology, 71, 793-801. [Google Scholar] [CrossRef] [PubMed]
[3] Binet, Q., Loumaye, A., Preumont, V., Thissen, J., Hermans, M.P. and Lanthier, N. (2022) Non-Invasive Screening, Staging and Management of Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD) in Type 2 Diabetes Mellitus Patients: What Do We Know So Far? Acta Gastro Enterologica Belgica, 85, 346-357. [Google Scholar] [CrossRef] [PubMed]
[4] Choudhury, J. and Sanyal, A.J. (2004) Insulin Resistance and the Pathogenesis of Nonalcoholic Fatty Liver Disease. Clinics in Liver Disease, 8, 575-594. [Google Scholar] [CrossRef] [PubMed]
[5] Kan, M., Fu, H., Xu, Y., Yue, Z., Du, B., Chen, Q., et al. (2023) Effects of Once‐Weekly Glucagon‐Like Peptide‐1 Receptor Agonists on Type 2 Diabetes Mellitus Complicated with Coronary Artery Disease: Potential Role of the Renin‐angiotensin System. Diabetes, Obesity and Metabolism, 25, 3223-3234. [Google Scholar] [CrossRef] [PubMed]
[6] Nomoto, H., Takahashi, Y., Takano, Y., Yokoyama, H., Tsuchida, K., Nagai, S., et al. (2023) Effect of Switching to Once-Weekly Semaglutide on Non-Alcoholic Fatty Liver Disease: The SWITCH-SEMA 1 Subanalysis. Pharmaceutics, 15, Article 2163. [Google Scholar] [CrossRef] [PubMed]
[7] Lamos, E.M., Kristan, M., Siamashvili, M. and Davis, S.N. (2021) Effects of Anti-Diabetic Treatments in Type 2 Diabetes and Fatty Liver Disease. Expert Review of Clinical Pharmacology, 14, 837-852. [Google Scholar] [CrossRef] [PubMed]
[8] Miao, L., Xu, J., Targher, G., Byrne, C.D. and Zheng, M. (2022) Old and New Classes of Glucose-Lowering Agents as Treatments for Non-Alcoholic Fatty Liver Disease: A Narrative Review. Clinical and Molecular Hepatology, 28, 725-738. [Google Scholar] [CrossRef] [PubMed]
[9] Zachou, M., Flevari, P., Nasiri-Ansari, N., Varytimiadis, C., Kalaitzakis, E., Kassi, E., et al. (2023) The Role of Anti-Diabetic Drugs in NAFLD. Have We Found the Holy Grail? A Narrative Review. European Journal of Clinical Pharmacology, 80, 127-150. [Google Scholar] [CrossRef] [PubMed]
[10] Wang, X., Shen, Y., Wang, S., Li, S., Zhang, W., Liu, X., et al. (2017) PharmMapper 2017 Update: A Web Server for Potential Drug Target Identification with a Comprehensive Target Pharmacophore Database. Nucleic Acids Research, 45, W356-W360. [Google Scholar] [CrossRef] [PubMed]
[11] Yao, Z., Dong, J., Che, Y., Zhu, M., Wen, M., Wang, N., et al. (2016) TargetNet: A Web Service for Predicting Potential Drug-Target Interaction Profiling via Multi-Target SAR Models. Journal of Computer-Aided Molecular Design, 30, 413-424. [Google Scholar] [CrossRef] [PubMed]
[12] Keiser, M.J., Roth, B.L., Armbruster, B.N., Ernsberger, P., Irwin, J.J. and Shoichet, B.K. (2007) Relating Protein Pharmacology by Ligand Chemistry. Nature Biotechnology, 25, 197-206. [Google Scholar] [CrossRef] [PubMed]
[13] Gilson, M.K., Liu, T., Baitaluk, M., Nicola, G., Hwang, L. and Chong, J. (2015) BindingDB in 2015: A Public Database for Medicinal Chemistry, Computational Chemistry and Systems Pharmacology. Nucleic Acids Research, 44, D1045-D1053. [Google Scholar] [CrossRef] [PubMed]
[14] Stelzer, G., Rosen, N., Plaschkes, I., Zimmerman, S., Twik, M., Fishilevich, S., et al. (2016) The GeneCards Suite: From Gene Data Mining to Disease Genome Sequence Analyses. Current Protocols in Bioinformatics, 54, 1.30.1-1.30.33. [Google Scholar] [CrossRef] [PubMed]
[15] Piñero, J., et al. (2020) The DisGeNET Knowledge Platform for Disease Genomics: 2019 Update. Nucleic Acids Research, 48, D845-D855.
[16] Consortium, U. (2023) UniProt: The Universal Protein Knowledgebase in 2023. Nucleic Acids Research, 51, D523-D531.
[17] Shannon, P., Markiel, A., Ozier, O., Baliga, N.S., Wang, J.T., Ramage, D., et al. (2003) Cytoscape: A Software Environment for Integrated Models of Biomolecular Interaction Networks. Genome Research, 13, 2498-2504. [Google Scholar] [CrossRef] [PubMed]
[18] Szklarczyk, D., Gable, A.L., Lyon, D., Junge, A., Wyder, S., Huerta-Cepas, J., et al. (2018) STRING V11: Protein-Protein Association Networks with Increased Coverage, Supporting Functional Discovery in Genome-Wide Experimental Datasets. Nucleic Acids Research, 47, D607-D613. [Google Scholar] [CrossRef] [PubMed]
[19] Tang, D., Chen, M., Huang, X., Zhang, G., Zeng, L., Zhang, G., et al. (2023) SRplot: A Free Online Platform for Data Visualization and Graphing. PLOS ONE, 18, e0294236. [Google Scholar] [CrossRef] [PubMed]
[20] Clayton-Chubb, D., Kemp, W., Majeed, A., Lubel, J.S., Hodge, A. and Roberts, S.K. (2023) Understanding NAFLD: From Case Identification to Interventions, Outcomes, and Future Perspectives. Nutrients, 15, Article 687. [Google Scholar] [CrossRef] [PubMed]
[21] Asadipooya, K. and Uy, E.M. (2019) Advanced Glycation End Products (ages), Receptor for Ages, Diabetes, and Bone: Review of the Literature. Journal of the Endocrine Society, 3, 1799-1818. [Google Scholar] [CrossRef] [PubMed]
[22] Taguchi, K. and Fukami, K. (2023) RAGE Signaling Regulates the Progression of Diabetic Complications. Frontiers in Pharmacology, 14, Article 1128872. [Google Scholar] [CrossRef] [PubMed]
[23] Berkovic, M.C., Virovic-Jukic, L., Bilic-Curcic, I. and Mrzljak, A. (2020) Post-Transplant Diabetes Mellitus and Preexisting Liver Disease—A Bidirectional Relationship Affecting Treatment and Management. World Journal of Gastroenterology, 26, 2740-2757. [Google Scholar] [CrossRef] [PubMed]
[24] Tang, S., Zhang, Q., Tang, H., Wang, C., Su, H., Zhou, Q., et al. (2016) Effects of Glucagon-Like Peptide-1 on Advanced Glycation Endproduct-Induced Aortic Endothelial Dysfunction in Streptozotocin-Induced Diabetic Rats: Possible Roles of Rho Kinase-and AMP Kinase-Mediated Nuclear Factor κB Signaling Pathways. Endocrine, 53, 107-116. [Google Scholar] [CrossRef] [PubMed]
[25] Wei, R., Ma, S., Wang, C., Ke, J., Yang, J., Li, W., et al. (2016) Exenatide Exerts Direct Protective Effects on Endothelial Cells through the AMPK/Akt/eNOS Pathway in a GLP-1 Receptor-Dependent Manner. American Journal of Physiology-Endocrinology and Metabolism, 310, E947-E957. [Google Scholar] [CrossRef] [PubMed]
[26] Wu, Y., Ma, K.L., Zhang, Y., Wen, Y., Wang, G.H., Hu, Z.B., et al. (2016) Lipid Disorder and Intrahepatic Renin-Angiotensin System Activation Synergistically Contribute to Non‐Alcoholic Fatty Liver Disease. Liver International, 36, 1525-1534. [Google Scholar] [CrossRef] [PubMed]
[27] Mkhize, B.C., Mosili, P., Ngubane, P.S., Sibiya, N.H. and Khathi, A. (2023) The Relationship between Renin-Angiotensin-Aldosterone System (RAAS) Activity, Osteoporosis and Estrogen Deficiency in Type 2 Diabetes. International Journal of Molecular Sciences, 24, Article ID: 11963. [Google Scholar] [CrossRef] [PubMed]
[28] Mastoor, Z., Diz-Chaves, Y., González-Matías, L.C. and Mallo, F. (2022) Renin-Angiotensin System in Liver Metabolism: Gender Differences and Role of Incretins. Metabolites, 12, Article 411. [Google Scholar] [CrossRef] [PubMed]
[29] Yang, M., Ma, X., Xuan, X., Deng, H., Chen, Q. and Yuan, L. (2020) Liraglutide Attenuates Non-Alcoholic Fatty Liver Disease in Mice by Regulating the Local Renin-Angiotensin System. Frontiers in Pharmacology, 11, Article 432. [Google Scholar] [CrossRef] [PubMed]
[30] Rajapaksha, I.G., Gunarathne, L.S., Asadi, K., Laybutt, R., Andrikopoulous, S., Alexander, I.E., et al. (2021) Angiotensin Converting Enzyme‐2 Therapy Improves Liver Fibrosis and Glycemic Control in Diabetic Mice with Fatty Liver. Hepatology Communications, 6, 1056-1072. [Google Scholar] [CrossRef] [PubMed]
[31] Tanase, D.M., Gosav, E.M., Costea, C.F., Ciocoiu, M., Lacatusu, C.M., Maranduca, M.A., et al. (2020) The Intricate Relationship between Type 2 Diabetes Mellitus (T2DM), Insulin Resistance (IR), and Nonalcoholic Fatty Liver Disease (NAFLD). Journal of Diabetes Research, 2020, Article ID: 3920196. [Google Scholar] [CrossRef] [PubMed]
[32] Fujii, H. and Kawada, N. (2020) The Role of Insulin Resistance and Diabetes in Nonalcoholic Fatty Liver Disease. International Journal of Molecular Sciences, 21, Article 3863. [Google Scholar] [CrossRef] [PubMed]
[33] Fang, L., Li, J., Zeng, H. and Liu, J. (2024) Effects of GLP-1 Receptor Agonists on the Degree of Liver Fibrosis and CRP in Non-Alcoholic Fatty Liver Disease and Non-Alcoholic Steatohepatitis: A Systematic Review and Meta-Analysis. Primary Care Diabetes, 18, 268-276. [Google Scholar] [CrossRef] [PubMed]
[34] Wang, X.J. and Malhi, H. (2018) Nonalcoholic Fatty Liver Disease. Annals of Internal Medicine, 169, ITC65-ITC80. [Google Scholar] [CrossRef] [PubMed]