2-酰基甘油O-酰基转移酶2在代谢相关脂肪性肝病中的作用机制及相关靶向治疗

贺晶晶; 张欣怡; 丁娜; 郝娅男; 郑亚; 姬瑞

doi:10.12449/JCH260726

2-酰基甘油O-酰基转移酶2在代谢相关脂肪性肝病中的作用机制及相关靶向治疗

DOI: 10.12449/JCH260726

贺晶晶^{1, 2},
张欣怡^{1, 2},
丁娜^{1, 2},
郝娅男^{1, 2},
郑亚²,
姬瑞^2, , ,

1.
兰州大学第一临床医学院，兰州 730000
2.
兰州大学第一医院消化科，甘肃省消化系疾病临床医学研究中心，兰州 730000

基金项目:

中央引导地方科技发展资金项目 (25ZYJA02)

利益冲突声明：本文不存在任何利益冲突。

作者贡献声明：贺晶晶负责设计论文框架，起草论文；张欣怡、丁娜和郝娅男负责文献检索及整理；郑亚、姬瑞负责论文修改，指导撰写文章并最后定稿。

详细信息

通信作者:
姬瑞， jir@lzu.edu.cn （ORCID： 0000-0001-9011-2222）

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出版历程
- 收稿日期: 2025-10-23
- 录用日期: 2025-11-25
- 出版日期: 2026-07-25

Mechanism of action of 2-acylglycerol O-acyltransferase 2 in metabolic associated fatty liver disease and related targeted therapies

Jingjing He^{1, 2},
Xinyi Zhang^{1, 2},
Na Ding^{1, 2},
Yanan Hao^{1, 2},
Ya Zheng²,
Rui Ji^{2
, ,
,}

1.
The First Clinical Medical College of Lanzhou University，Lanzhou 730000，China
2.
Department of Gastroenterology，Gansu Province Clinical Research Center for Digestive Diseases，The First Hospital of Lanzhou University，Lanzhou 730000，China

Research funding:

Central Government Guiding Local Scientific and Technological Development Fund (25ZYJA02)

More Information

Corresponding author: Ji Rui， jir@lzu.edu.cn （ORCID： 0000-0001-9011-2222）

摘要

摘要: 代谢相关脂肪性肝病已成为全球范围内流行的慢性肝病之一，其核心病理特征是肝细胞内甘油三酯的病理性蓄积，而2-酰基甘油O-酰基转移酶（DGAT） 2 作为肝脏催化甘油三酯合成的关键限速酶，在该过程中扮演核心角色。细胞和动物模型研究证实，抑制DGAT2可有效改善肝脂肪变性并延缓疾病进展，后续临床试验亦表现出治疗代谢相关脂肪性肝病的潜在临床应用价值。本综述系统探讨了DGAT2在代谢相关脂肪性肝病发生发展中的作用机制，并全面总结靶向DGAT2的治疗策略，包括单药干预和联合用药的研究进展，以期为代谢相关脂肪性肝病患者的个性化治疗提供新思路。
- 代谢相关脂肪性肝病 /
- 2-酰基甘油O-酰基转移酶2 /
- 分子靶向治疗
Abstract: Metabolic associated fatty liver disease （MAFLD） has become one of the most prevalent chronic liver diseases worldwide， with the core pathological feature of pathological accumulation of triglycerides in hepatocytes， and as a key rate-limiting enzyme for triglyceride synthesis in the liver， 2-acylglycerol O-acyltransferase 2 （DGAT2） plays a central role in this process. Cell and animal model studies have confirmed that inhibition of DGAT2 can effectively alleviate hepatic steatosis and delay disease progression， and subsequent clinical trials have also shown the potential clinical application value in the treatment of MAFLD. This article systematically reviews the mechanism of action of DGAT2 in the development and progression of MAFLD and comprehensively summarizes the therapeutic strategies targeting DGAT2， including the advances in both monotherapy and drug combinations， in order to provide new ideas for individualized treatment of MAFLD patients.
- Metabolic Dysfunction-Associated Fatty Liver Disease /
- 2-Acylglycerol O-Acyltransferase 2 /
- Molecular Targeted Therapy

HTML全文

注： DGAT2，2-酰基甘油O-酰基转移酶2；TG，甘油三酯；DAG，二酰甘油；FFA，游离脂肪酸；ER，内质网；DNL，脂肪从头合成；SREBP-1c，固醇调节元件结合蛋白1c；ChREBP，碳水化合物反应元件结合蛋白；XBP1，X盒结合蛋白1；CoA，辅酶A；MASH，代谢相关脂肪性肝炎；PNPLA3，含Patatin样磷脂酶域蛋白3；TM6SF2，跨膜6超家族成员2；MAFLD，代谢相关脂肪性肝病。

图 1 DGAT2在MAFLD中的作用机制

Figure 1. The mechanism of DGAT2 in MAFLD

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表 1 靶向DGAT2的代表性药物临床试验概况

Table 1. Overview of clinical trials for representative drugs targeting DGAT2

药物名称	类型	研发阶段	关键结果
IONIS-DGAT2 Rx（ISIS 484137）	反义寡核苷酸	Ⅱ期	有效降低合并肥胖、2型糖尿病MAFLD患者的肝脏脂肪含量，未引发高脂血症等不良反应^［23］
ION224	反义寡核苷酸	Ⅱ期	使MASH和早期纤维化患者NAS降低≥2分、肝细胞气样变或小叶炎症至少改善1分，且纤维化无恶化；达到MASH缓解和纤维化改善；且糖化血红蛋白、肝酶呈下降趋势^［14］
PF-06427878	小分子抑制剂	Ⅰ期	显著降低肝脏脂肪含量，改善肝功能，耐受良好，无严重不良反应；但因儿茶酚代谢物释放风险未进一步开发^［25］
Ervogastat（PF-06865571）	小分子抑制剂	Ⅱ期	在Ⅰ期试验的NAFLD患者中降低肝脏脂肪含量24.3%～ 33.9%；但在Ⅱ期MASH和早期纤维化患者中未达到MASH 缓解或纤维化未恶化的主要终点^［4，26］
PF-07202954	小分子抑制剂	将进入临床试验	在保持DGAT2高选择性与强效的基础上具有更长的半衰期^［27］
Ervogastat（PF-06865571）+ Clesacostat（PF-05221304）	联合抑制DGAT2和 ACC	Ⅱ期	联合用药肝脏脂肪降低幅度和应答率高于单药，且抵消了 ACC抑制剂引起的血浆TG升高；在MASH患者中显示出比安慰剂更强的组织学改善趋势^{［26，30］}
注：MAFLD，代谢相关脂肪性肝病；MASH，代谢相关脂肪性肝炎；NAS，非酒精性脂肪肝活动度评分；DGAT2，2-酰基甘油O-酰基转移酶；ACC，乙酰辅酶A羧化酶。

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