脂肪量和肥胖相关基因在代谢相关脂肪性肝病发生发展中的作用机制及相关靶向治疗

潘兆权; 刘旭东; 谭伟强; 冉小柯; 袁媛; 娄鑫凤

doi:10.12449/JCH250625

脂肪量和肥胖相关基因在代谢相关脂肪性肝病发生发展中的作用机制及相关靶向治疗

DOI: 10.12449/JCH250625

1.
广西中医药大学研究生院，南宁 530004
2.
广西中医药大学附属瑞康医院肝病科，南宁 530022

基金项目:

国家自然科学基金 (82160837);

广西中医药大学岐黄工程高层次人才培育项目 (2021007)

利益冲突声明：本文不存在任何利益冲突。

作者贡献声明：潘兆权负责课题设计，资料分析，撰写论文；谭伟强、冉小柯、袁媛、娄鑫凤参与整理文献，修改论文；刘旭东指导撰写文章并最后定稿。

详细信息

通信作者:
刘旭东， lxdlhx@163.com （ORCID： 0000-0003-1468-0484）

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出版历程
- 收稿日期: 2024-09-26
- 录用日期: 2024-10-28
- 出版日期: 2025-06-25

Mechanism of action of the fat mass and obesity-associated gene in the development and progression of metabolic dysfunction-associated fatty liver disease and related targeted therapies

1.
Graduate School of Guangxi University of Chinese Medicine，Nanning 530004，China
2.
Department of Hepatology，Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine，Nanning 530022，China

Research funding:

National Natural Science Foundation of China (82160837);

Guangxi University of Traditional Chinese Medicine Qihuang Engineering High-level Talent Cultivation Project (2021007)

More Information

Corresponding author: LIU Xudong， lxdlhx@163.com （ORCID： 0000-0003-1468-0484）

摘要

摘要: 代谢相关（非酒精性）脂肪性肝病（MAFLD）是一种常见的慢性肝脏疾病，其病理特征为肝脏内脂质堆积，且与肝脏代谢紊乱密切相关。最新研究表明，MAFLD的发生机制与特定基因的异常表达有关，特别是脂肪量和肥胖相关基因（FTO）。FTO基因表达的异常升高可能导致肝脂质代谢失衡，表现为脂肪酸合成增加和氧化减少，从而促进肝脂肪沉积和炎症反应。因此，调控FTO基因的表达或活性被认为是治疗MAFLD的潜在策略之一。目前，针对FTO基因功能的药物研究初见成效，可通过抑制FTO基因的活性，调节肝脂质代谢，并减轻肝脏的炎症损伤。本文综述了FTO基因在MAFLD发生发展中的作用机制，并总结了近年来围绕FTO基因及其相关代谢通路的药物研究进展，并展望其在该领域研究和治疗中的应用前景。
- α酮戊二酸依赖性双加氧酶FTO /
- 非酒精性脂肪性肝病 /
- 脂代谢障碍 /
- 基因治疗
Abstract: Metabolic dysfunction-associated fatty liver disease （MAFLD） is a common chronic liver disease with the pathological feature of lipid accumulation in the liver， and it is closely associated with liver metabolic disorders. The latest research has shown that the pathogenesis of MAFLD is associated with the abnormal expression of specific genes， especially the fat mass and obesity-associated （FTO） gene. The abnormal activity of the FTO gene may lead to an imbalance in liver lipid metabolism， which manifests as the increase in fatty acid synthesis and the reduction in fatty acid oxidation， thereby promoting liver fat deposition and inflammatory response. Therefore， regulating the expression or activity of the FTO gene is considered one of the potential strategies for the treatment of MAFLD. At present， drug research targeting the function of the FTO gene has achieved preliminary results， and inhibition of the activity of the FTO gene can help to regulate liver lipid metabolism and alleviate liver inflammatory injury. This article reviews the mechanism of action of the FTO gene in the development and progression of MAFLD， summarizes the advances in drug research on the FTO gene and related metabolic pathways in recent years， and analyzes their application prospect in research and treatment.
- Alpha-Ketoglutarate-Dependent Dioxygenase FTO /
- Non-alcoholic Fatty Liver Disease /
- Lipid Metabolism Disorders /
- Genetic Therapy

HTML全文

注： FXR，法尼醇X受体；SCD1，硬脂酰辅酶A去饱和酶1；MGAT1，单酰基甘油酰基转移酶1；MTTP，微粒体甘油三酯转运蛋白；APOB，载脂蛋白B；LIPC，肝脂酶。

图 1 FTO基因调控脂肪生成机制图

Figure 1. Mechanism of FTO gene regulates lipogenesis genes

下载: 全尺寸图片幻灯片

表 1 FTO基因治疗MAFLD相关药物/分子

Table 1. Related drugs/molecules for FTO treatment of MAFLD

分类	药物/分子	作用机制	应用潜力	参考文献
天然类	熊果苷	抑制FTO基因去甲基化酶活性，增加m⁶A 甲基化水平，调节脂质代谢相关基因表达，减少肝脂肪积累	具有天然来源和低毒性，适用于长期治疗的MAFLD药物	［44-46］
天然类	TMG	增加m⁶A甲基化水平，减少脂肪堆积，调节脂质代谢	预防脂质代谢紊乱，治疗MAFLD	［50-51］
非天然类（药物类）	EXN	激活GLP-1受体，启动PI3K/AKT信号通路，抑制FTO基因表达，减少脂肪堆积和炎症反应	作为糖尿病和MAFLD的双效药物，改善肝脂肪堆积，减轻炎症	［41-43］
	COMT-Is	通过抑制FTO基因去甲基化酶活性，增加 m⁶A甲基化水平，调节脂质代谢相关基因表达，减少脂肪积累	显著改善MAFLD，潜在治疗其他脂质代谢相关疾病的药物	［38，47-48］
	DCS	调节FTO基因表达，影响m⁶A水平和肝脂质代谢	治疗MAFLD，具有潜在应用价值	［50-51］
非天然类（非编码RNA 及其载体）	miRNA	通过抑制FTO基因表达，调节脂质代谢，如 miR-627-5p、miR-143、miR-30b	个性化治疗的潜力，可能改善MAFLD 和其他代谢性疾病	［53-54］
非天然类（非编码RNA 及其载体）	外泌体	通过靶向FTO基因，调控葡萄糖和脂质代谢，改善MAFLD	作为MAFLD治疗的创新方法，可能为新型治疗提供思路	［52］

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