GLP-1受体激动剂在代谢功能障碍相关脂肪性肝病治疗中的研究进展
Research Progress of GLP-1 Receptor Agonists in the Treatment of Metabolic Dysfunction-Associated Steatotic Liver Disease
DOI: 10.12677/jcpm.2025.43402, PDF,   
作者: 陈舒婷:湖南师范大学附属第一医院(湖南省人民医院)内分泌科,湖南 长沙;刘 瑛, 张 弛*:湖南省人民医院(湖南师范大学附属第一医院)内分泌科,湖南 长沙
关键词: 代谢功能障碍相关脂肪性肝病胰高血糖素样肽-1受体激动剂肝纤维化肝脂肪变性胰岛素抵抗Metabolic Dysfunction-Associated Fatty Liver Disease Glucagon-Like Peptide-1 Receptor Agonists Liver Fibrosis Hepatic Steatosis Insulin Resistance
摘要: 代谢功能障碍相关脂肪性肝病(MASLD)是一种与多种代谢异常密切相关的慢性肝脏疾病,其核心病理特征为脂肪在肝细胞内异常堆积,且排除其他已知致病因素,如酒精性肝病、病毒性肝炎及自身免疫性疾病等。MASLD与代谢综合征和2型糖尿病之间相互影响,共同促进动脉粥样硬化性心脏病、慢性肾脏病及肝细胞癌等恶性肿瘤等多种并发症的发生。这种复杂的代谢网络使得MASLD成为日益严峻的公共卫生问题。2024年,瑞美替罗成为首个获美国食品药品监督管理局批准用于治疗MASH的药物,然而针对MASLD的早期阶段仍缺乏获批药物。在此背景下,胰高血糖素样肽-1 (GLP-1)受体激动剂因其独特的多靶点调控作用,在MASLD治疗中展现出显著的临床应用潜力。本研究旨在系统分析GLP-1受体激动剂在MASLD治疗中的作用机制,并结合循证医学证据评估其疗效与安全性,为临床实践提供理论依据。
Abstract: Metabolic dysfunction-associated fatty liver disease (MASLD) is a chronic liver disease closely related to a variety of metabolic abnormalities, and its core pathological feature is abnormal accumulation of fat in hepatocytes, and other known pathogenic factors, such as alcoholic liver disease, viral hepatitis and autoimmune diseases, are excluded. MASLD interacts with metabolic syndrome and type 2 diabetes mellitus, and jointly promotes the occurrence of various complications such as atherosclerotic heart disease, chronic kidney disease, and hepatocellular carcinoma. This complex metabolic network makes MASLD a growing public health problem. In 2024, remettirol became the first drug approved by the U.S. Food and Drug Administration for the treatment of MASH, although there is still a lack of approved drugs for MASLD in the early stages. In this context, glucagon-like peptide-1 (GLP-1) receptor agonists have shown significant clinical application potential in the treatment of MASLD due to their unique multi-target regulatory effects. The purpose of this study was to systematically analyze the mechanism of action of GLP-1 receptor agonists in the treatment of MASLD, and to evaluate their efficacy and safety based on evidence-based medical evidence, so as to provide a theoretical basis for clinical practice.
文章引用:陈舒婷, 刘瑛, 张弛. GLP-1受体激动剂在代谢功能障碍相关脂肪性肝病治疗中的研究进展[J]. 临床个性化医学, 2025, 4(3): 730-738. https://doi.org/10.12677/jcpm.2025.43402

参考文献

[1] Bai, J., Zhu, L., Mi, W., Gao, Z., Ouyang, M., Sheng, W., et al. (2023) Multiscale Integrative Analyses Unveil Immune-Related Diagnostic Signature for the Progression of MASLD. Hepatology Communications, 7, e0298. [Google Scholar] [CrossRef] [PubMed]
[2] Yagüe-Caballero, C., Casas-Deza, D., Pascual-Oliver, A., Espina-Cadena, S., Arbones-Mainar, J.M. and Bernal-Monterde, V. (2024) MASLD-Related Hepatocarcinoma: Special Features and Challenges. Journal of Clinical Medicine, 13, Article 4657. [Google Scholar] [CrossRef] [PubMed]
[3] Dai, J., Liu, Y. and Zhang, Z. (2024) Changes in the Etiology of Liver Cirrhosis and the Corresponding Management Strategies. World Journal of Hepatology, 16, 146-151. [Google Scholar] [CrossRef] [PubMed]
[4] European Association for the Study of the Liver (EASL), European Association for the Study of Diabetes (EASD) and European Association for the Study of Obesity (EASO) (2024) EASL-EASD-EASO Clinical Practice Guidelines on the Management of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD). Obesity Facts, 17, 374-444. [Google Scholar] [CrossRef] [PubMed]
[5] Kimura, Y., Tapia Sosa, R., Soto-Trujillo, D., Kimura Sandoval, Y. and Casian, C. (2020) Liver Transplant Complications Radiologist Can’t Miss. Cureus, 12, e8465. [Google Scholar] [CrossRef] [PubMed]
[6] Mellemkjær, A., Kjær, M.B., Haldrup, D., Grønbæk, H. and Thomsen, K.L. (2024) Management of Cardiovascular Risk in Patients with Metabolic Dysfunction-Associated Steatotic Liver Disease. European Journal of Internal Medicine, 122, 28-34. [Google Scholar] [CrossRef] [PubMed]
[7] Targher, G., Byrne, C.D. and Tilg, H. (2024) MASLD: A Systemic Metabolic Disorder with Cardiovascular and Malignant Complications. Gut, 73, 691-702. [Google Scholar] [CrossRef] [PubMed]
[8] Hagström, H., Vessby, J., Ekstedt, M. and Shang, Y. (2024) 99% of Patients with NAFLD Meet MASLD Criteria and Natural History Is Therefore Identical. Journal of Hepatology, 80, e76-e77. [Google Scholar] [CrossRef] [PubMed]
[9] Ossima, A.N., Brzustowski, A., Paradis, V., Van Beers, B., Postic, C., Laouénan, C., et al. (2024) Factors Associated with High Costs of Patients with Metabolic Dysfunction-Associated Steatotic Liver Disease: An Observational Study Using the French Constances Cohort. Clinical Diabetes and Endocrinology, 10, Article No. 9. [Google Scholar] [CrossRef] [PubMed]
[10] Ang, S.M., Lim, S.L., Dan, Y.Y., Chan, Y.H., Yap, Q.V. and Chen, J. (2024) Clinical Service Incorporating Mobile Technology on Weight Loss in Patients with Metabolic Dysfunction-Associated Steatotic Liver Disease: A Translation from Research Trial. Endocrinology, Diabetes & Metabolism, 7, e00485. [Google Scholar] [CrossRef] [PubMed]
[11] de Avila, L., Henry, L., Paik, J.M., Ijaz, N., Weinstein, A.A. and Younossi, Z.M. (2023) Nonalcoholic Fatty Liver Disease Is Independently Associated with Higher All-Cause and Cause-Specific Mortality. Clinical Gastroenterology and Hepatology, 21, 2588-2596.e3. [Google Scholar] [CrossRef] [PubMed]
[12] Hu, Y., Zai, H., Jiang, W., Ou, Z., Yao, Y. and Zhu, Q. (2021) The Mutual Inhibition of FoxO1 and SREBP-1c Regulated the Progression of Hepatoblastoma by Regulating Fatty Acid Metabolism. Mediators of Inflammation, 2021, Article 5754592. [Google Scholar] [CrossRef] [PubMed]
[13] Shreya, S., Grosset, C.F. and Jain, B.P. (2023) Unfolded Protein Response Signaling in Liver Disorders: A 2023 Updated Review. International Journal of Molecular Sciences, 24, Article 14066. [Google Scholar] [CrossRef] [PubMed]
[14] Khan, M.S., Lee, C. and Kim, S.G. (2022) Non-Alcoholic Fatty Liver Disease and Liver Secretome. Archives of Pharmacal Research, 45, 938-963. [Google Scholar] [CrossRef] [PubMed]
[15] Liao, M., Zhang, R., Wang, Y., Mao, Z., Wu, J., Guo, H., et al. (2022) Corilagin Prevents Non-Alcoholic Fatty Liver Disease via Improving Lipid Metabolism and Glucose Homeostasis in High Fat Diet-Fed Mice. Frontiers in Nutrition, 9, Article 983450. [Google Scholar] [CrossRef] [PubMed]
[16] Shin, S., Kim, J., Lee, J.Y., Kim, J. and Oh, C. (2023) Mitochondrial Quality Control: Its Role in Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD). Journal of Obesity & Metabolic Syndrome, 32, 289-302. [Google Scholar] [CrossRef] [PubMed]
[17] Koyama, H., Kamogashira, T. and Yamasoba, T. (2024) Heavy Metal Exposure: Molecular Pathways, Clinical Implications, and Protective Strategies. Antioxidants, 13, Article 76. [Google Scholar] [CrossRef] [PubMed]
[18] Liu, S., Ding, H., Li, Y. and Zhang, X. (2022) Molecular Mechanism Underlying Role of the XBP1s in Cardiovascular Diseases. Journal of Cardiovascular Development and Disease, 9, Article 459. [Google Scholar] [CrossRef] [PubMed]
[19] Teuwen, J.T.J., van der Vorst, E.P.C. and Maas, S.L. (2024) Navigating the Maze of Kinases: CaMK-Like Family Protein Kinases and Their Role in Atherosclerosis. International Journal of Molecular Sciences, 25, Article 6213. [Google Scholar] [CrossRef] [PubMed]
[20] Yang, J., Zhong, C. and Yu, J. (2023) Natural Monoterpenes as Potential Therapeutic Agents against Atherosclerosis. International Journal of Molecular Sciences, 24, Article 2429. [Google Scholar] [CrossRef] [PubMed]
[21] Ni, L., Yang, L. and Lin, Y. (2024) Recent Progress of Endoplasmic Reticulum Stress in the Mechanism of Atherosclerosis. Frontiers in Cardiovascular Medicine, 11, Article 1413441. [Google Scholar] [CrossRef] [PubMed]
[22] Yanai, H., Adachi, H., Hakoshima, M., Iida, S. and Katsuyama, H. (2023) Metabolic-Dysfunction-Associated Steatotic Liver Disease—Its Pathophysiology, Association with Atherosclerosis and Cardiovascular Disease, and Treatments. International Journal of Molecular Sciences, 24, Article 15473. [Google Scholar] [CrossRef] [PubMed]
[23] Qiu, F., Wang, J., Liu, H. and Zhang, Y. (2019) Mulberry Bark Alleviates Effect of STZ Inducing Diabetic Mice through Negatively Regulating FoxO1. Evidence-Based Complementary and Alternative Medicine, 2019, Article 2182865. [Google Scholar] [CrossRef] [PubMed]
[24] Yin, C., Liu, W.H., Liu, Y., Wang, L. and Xiao, Y. (2019) PID1 Alters the Antilipolytic Action of Insulin and Increases Lipolysis via Inhibition of AKT/PKA Pathway Activation. PLOS ONE, 14, e0214606. [Google Scholar] [CrossRef] [PubMed]
[25] Kim, M.J., Park, C.H., Kim, D.H., Park, M.H., Park, K.C., Hyun, M.K., et al. (2018) Hepatoprotective Effects of MHY3200 on High-Fat, Diet-Induced, Non-Alcoholic Fatty Liver Disease in Rats. Molecules, 23, Article 2057. [Google Scholar] [CrossRef] [PubMed]
[26] Parlevliet, E.T., Wang, Y., Geerling, J.J., Schröder-Van der Elst, J.P., Picha, K., O’Neil, K., et al. (2012) GLP-1 Receptor Activation Inhibits VLDL Production and Reverses Hepatic Steatosis by Decreasing Hepatic Lipogenesis in High-Fat-Fed APOE*3-Leiden Mice. PLOS ONE, 7, e49152. [Google Scholar] [CrossRef] [PubMed]
[27] Winarto, J., Song, D. and Pan, C. (2023) The Role of Fucoxanthin in Non-Alcoholic Fatty Liver Disease. International Journal of Molecular Sciences, 24, Article 8203. [Google Scholar] [CrossRef] [PubMed]
[28] Drożdż, K., Nabrdalik, K., Hajzler, W., Kwiendacz, H., Gumprecht, J. and Lip, G.Y.H. (2021) Metabolic-Associated Fatty Liver Disease (MAFLD), Diabetes, and Cardiovascular Disease: Associations with Fructose Metabolism and Gut Microbiota. Nutrients, 14, Article 103. [Google Scholar] [CrossRef] [PubMed]
[29] Chrysavgis, L.G., Kazanas, S., Bafa, K., Rozani, S., Koloutsou, M. and Cholongitas, E. (2024) Glucagon-Like Peptide 1, Glucose-Dependent Insulinotropic Polypeptide, and Glucagon Receptor Agonists in Metabolic Dysfunction-Associated Steatotic Liver Disease: Novel Medication in New Liver Disease Nomenclature. International Journal of Molecular Sciences, 25, Article 3832. [Google Scholar] [CrossRef] [PubMed]
[30] Elshaer, A., Chascsa, D.M.H. and Lizaola-Mayo, B.C. (2024) Exploring Varied Treatment Strategies for Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD). Life, 14, Article 844. [Google Scholar] [CrossRef] [PubMed]
[31] Zhu, Y., Xu, J., Zhang, D., Mu, X., Shi, Y., Chen, S., et al. (2021) Efficacy and Safety of GLP-1 Receptor Agonists in Patients with Type 2 Diabetes Mellitus and Non-Alcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis. Frontiers in Endocrinology, 12, Article 769069. [Google Scholar] [CrossRef] [PubMed]
[32] Liu, J., Kang, R. and Tang, D. (2021) Signaling Pathways and Defense Mechanisms of Ferroptosis. The FEBS Journal, 289, 7038-7050. [Google Scholar] [CrossRef] [PubMed]
[33] Kalavalapalli, S., Bril, F., Guingab, J., Vergara, A., Garrett, T.J., Sunny, N.E., et al. (2019) Impact of Exenatide on Mitochondrial Lipid Metabolism in Mice with Nonalcoholic Steatohepatitis. Journal of Endocrinology, 241, 293-305. [Google Scholar] [CrossRef] [PubMed]
[34] Zhao, Y., Chen, L., Huang, L., Li, Y., Yang, C., Zhu, Y., et al. (2022) Cardiovascular Protective Effects of GLP-1: A Focus on the MAPK Signaling Pathway. Biochemistry and Cell Biology, 100, 9-16. [Google Scholar] [CrossRef] [PubMed]
[35] Delrue, C. and Speeckaert, M.M. (2024) Mechanistic Pathways and Clinical Implications of GLP-1 Receptor Agonists in Type 1 Diabetes Management. International Journal of Molecular Sciences, 25, Article 9351. [Google Scholar] [CrossRef] [PubMed]
[36] Okamoto, A., Yokokawa, H., Nagamine, T., Fukuda, H., Hisaoka, T. and Naito, T. (2021) Efficacy and Safety of Semaglutide in Glycemic Control, Body Weight Management, Lipid Profiles and Other Biomarkers among Obese Type 2 Diabetes Patients Initiated or Switched to Semaglutide from Other GLP-1 Receptor Agonists. Journal of Diabetes & Metabolic Disorders, 20, 2121-2128. [Google Scholar] [CrossRef] [PubMed]
[37] Shang, R. and Miao, J. (2023) Mechanisms and Effects of Metformin on Skeletal Muscle Disorders. Frontiers in Neurology, 14, Article 1275266. [Google Scholar] [CrossRef] [PubMed]
[38] Meloni, A.R., DeYoung, M.B., Lowe, C. and Parkes, D.G. (2012) GLP‐1 Receptor Activated Insulin Secretion from Pancreatic β‐Cells: Mechanism and Glucose Dependence. Diabetes, Obesity and Metabolism, 15, 15-27. [Google Scholar] [CrossRef] [PubMed]
[39] Guo, C., Huang, T., Chen, A., Chen, X., Wang, L., Shen, F., et al. (2016) Glucagon-Like Peptide 1 Improves Insulin Resistance in Vitro through Anti-Inflammation of Macrophages. Brazilian Journal of Medical and Biological Research, 49, e5826. [Google Scholar] [CrossRef] [PubMed]
[40] Liu, J., Yang, K., Yang, J., Xiao, W., Le, Y., Yu, F., et al. (2019) Liver-Derived Fibroblast Growth Factor 21 Mediates Effects of Glucagon-Like Peptide-1 in Attenuating Hepatic Glucose Output. EBioMedicine, 41, 73-84. [Google Scholar] [CrossRef] [PubMed]
[41] Gao, H., Song, Z., Zhao, Q., Wu, Y., Tang, S., Alahdal, M., et al. (2018) Pharmacological Effects of EGLP-1, a Novel Analog of Glucagon-Like Peptide-1, on Carbohydrate and Lipid Metabolism. Cellular Physiology and Biochemistry, 48, 1112-1122. [Google Scholar] [CrossRef] [PubMed]
[42] Ackeifi, C., Wang, P., Karakose, E., Manning Fox, J.E., González, B.J., Liu, H., et al. (2020) GLP-1 Receptor Agonists Synergize with DYRK1A Inhibitors to Potentiate Functional Human Β Cell Regeneration. Science Translational Medicine, 12, eaaw9996. [Google Scholar] [CrossRef] [PubMed]
[43] Nguyen, M., Asgharpour, A., Dixon, D.L., Sanyal, A.J. and Mehta, A. (2024) Emerging Therapies for MASLD and Their Impact on Plasma Lipids. American Journal of Preventive Cardiology, 17, Article 100638. [Google Scholar] [CrossRef] [PubMed]
[44] 中华医学会肝病学分会. 代谢相关(非酒精性)脂肪性肝病防治指南(2024年版) [J]. 中华肝脏病杂志, 2024, 32(5): 418-434.
[45] Lara-Romero, C. and Romero-Gómez, M. (2024) Treatment Options and Continuity of Care in Metabolic-Associated Fatty Liver Disease: A Multidisciplinary Approach. European Cardiology Review, 19, e06. [Google Scholar] [CrossRef] [PubMed]
[46] Tan, H.C., Dampil, O.A. and Marquez, M.M. (2022) Efficacy and Safety of Semaglutide for Weight Loss in Obesity without Diabetes: A Systematic Review and Meta-Analysis. Journal of the ASEAN Federation of Endocrine Societies, 37, 65-72. [Google Scholar] [CrossRef] [PubMed]
[47] Feng, X., Zhang, R., Yang, Z., Zhang, K. and Xing, J. (2024) Mechanism of Metabolic Dysfunction-Associated Steatotic Liver Disease: Important Role of Lipid Metabolism. Journal of Clinical and Translational Hepatology, 12, 815-826. [Google Scholar] [CrossRef] [PubMed]
[48] Bjerre Knudsen, L., Madsen, L.W., Andersen, S., Almholt, K., de Boer, A.S., Drucker, D.J., et al. (2010) Glucagon-Like Peptide-1 Receptor Agonists Activate Rodent Thyroid C-Cells Causing Calcitonin Release and C-Cell Proliferation. Endocrinology, 151, 1473-1486. [Google Scholar] [CrossRef] [PubMed]
[49] Sun, Y., Liu, Y., Dian, Y., Zeng, F., Deng, G. and Lei, S. (2024) Association of Glucagon-Like Peptide-1 Receptor Agonists with Risk of Cancers-Evidence from a Drug Target Mendelian Randomization and Clinical Trials. International Journal of Surgery, 110, 4688-4694. [Google Scholar] [CrossRef] [PubMed]
[50] Manuel, S.L., Lin, F. and Kutty, S.M. (2023) An Atypical Presentation of Dulaglutide-Induced Pancreatitis Complicated by Superior Mesenteric Vein Thrombosis. Cureus, 15, e50051. [Google Scholar] [CrossRef] [PubMed]
[51] Zhu, Y., Xu, J., Zhang, D., Mu, X., Shi, Y., Chen, S., et al. (2021) Efficacy and Safety of GLP-1 Receptor Agonists in Patients with Type 2 Diabetes Mellitus and Non-Alcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis. Frontiers in Endocrinology, 12, Article 769069. [Google Scholar] [CrossRef] [PubMed]
[52] Lyu, B., Hwang, Y.J., Selvin, E., Jameson, B.C., Chang, A.R., Grams, M.E., et al. (2023) Glucose-Lowering Agents and the Risk of Hypoglycemia: A Real-World Study. Journal of General Internal Medicine, 38, 107-114. [Google Scholar] [CrossRef] [PubMed]
[53] Yabut, J.M. and Drucker, D.J. (2022) Glucagon-Like Peptide-1 Receptor-Based Therapeutics for Metabolic Liver Disease. Endocrine Reviews, 44, 14-32. [Google Scholar] [CrossRef] [PubMed]
[54] Kumarathurai, P., Anholm, C., Larsen, B.S., Olsen, R.H., Madsbad, S., Kristiansen, O., et al. (2016) Effects of Liraglutide on Heart Rate and Heart Rate Variability: A Randomized, Double-Blind, Placebo-Controlled Crossover Study. Diabetes Care, 40, 117-124. [Google Scholar] [CrossRef] [PubMed]
[55] Romera, I., Cebrián-Cuenca, A., Álvarez-Guisasola, F., Gomez-Peralta, F. and Reviriego, J. (2019) A Review of Practical Issues on the Use of Glucagon-Like Peptide-1 Receptor Agonists for the Management of Type 2 Diabetes. Diabetes Therapy, 10, 5-19. [Google Scholar] [CrossRef] [PubMed]
[56] Smits, M.M., van Raalte, D.H., Tonneijck, L., Muskiet, M.H.A., Kramer, M.H.H. and Cahen, D.L. (2016) GLP-1 Based Therapies: Clinical Implications for Gastroenterologists. Gut, 65, 702-711. [Google Scholar] [CrossRef] [PubMed]
[57] Begum, F., Chang, K., Kapoor, K., Vij, R., Phadke, G., Hiser, W.M., et al. (2024) Semaglutide-Associated Kidney Injury. Clinical Kidney Journal, 17, sfae250. [Google Scholar] [CrossRef] [PubMed]
[58] Smits, M.M. and Van Raalte, D.H. (2021) Safety of Semaglutide. Frontiers in Endocrinology, 12, Article 645563. [Google Scholar] [CrossRef] [PubMed]
[59] Huynh, D. (2023) Dual Metformin and Glucagon-Like Peptide-1 Receptor Agonist Therapy Reduces Mortality and Hepatic Complications in Cirrhotic Patients with Diabetes Mellitus. Annals of Gastroenterology, 36, 555-563. [Google Scholar] [CrossRef] [PubMed]