Research progress of acetylation in the pathogenesis of MASLD
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摘要:
代谢功能障碍相关脂肪性肝病（metabolic dysfunction-associated steatotic liver disease, MASLD）是全球最常见的慢性肝病病因，其发病机制复杂，导致新药研发困难。蛋白乙酰化修饰作为一种常见的翻译后修饰，参与调控蛋白质稳定性、酶活性及其亚细胞定位，广泛发生于MASLD相关的脂质代谢、炎症反应和氧化应激等病理生理过程。本文对相关蛋白质乙酰化修饰异常改变在MASLD中的作用机制进行了综述，分析了基因表达数据库（gene expression omnibus, GEO）中MASLD患者肝组织中（去）乙酰化酶的表达水平并讨论了相关酶在动物模型的表达变化及作用机制，进一步探讨了靶向蛋白乙酰化修饰治疗MASLD的可行性，为MASLD药物研发提供新思路。
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关键词:
- 代谢功能障碍相关脂肪性肝病 /
- 代谢功能障碍相关脂肪性肝炎 /
- 乙酰化 /
- 乙酰化酶
Abstract:Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent cause of chronic liver disease worldwide, and its intricate pathogenesis presents challenges in the development of new drugs. As a common way of post-translational modification, acetylation regulates protein stability, enzyme activity, and subcellular localization, occurring extensively in MASLD-associated processes such as lipid metabolism, inflammatory response, and oxidative stress. In this paper, we comprehensively review the mechanism of acetylation in MASLD, analyze the expression levels of acetylases in liver tissues of MASLD patients from the gene expression omnibus (GEO), discuss the changes in relevant enzyme expression and mechanisms in animal models, and further explore the feasibility of targeting acetylation for MASLD treatment, in the hope of offering a new perspective for advancing drug discovery in the field of MASLD.
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图 2 MASLD中的蛋白乙酰化/去乙酰化修饰（By Figdraw）
ChREBP：碳水化合物反应性元件结合蛋白；LDHB：乳酸脱氢酶B；FOXO1：叉头框蛋白O1；ACSL5：长链脂酰辅酶A合成酶5；ACLY：ATP-柠檬酸合酶；MnSOD：锰超氧化物歧化酶；TNF-α：肿瘤坏死因子-α；CCL2：趋化因子配体2
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图 3 MASLD患者肝脏中乙酰化酶和去乙酰化酶的转录水平（$\bar{x}\pm s $）
A:GCN5; B:HAT1; C:TIP60; D:SIRT1; E:SIRT5; F:HDAC1HC：健康对照人群；HO：健康肥胖人群；MAFL：代谢功能障碍相关脂肪肝患者；MASH：代谢功能障碍相关脂肪性肝炎患者；（来源于GDS4881数据集；HC：n = 14，HO：n = 27，MAFL：n = 14，MASH：n = 18； One-Way ANOVA；*P<0.05，**P<0.01，***P<0.001）
表 1 MASLD的临床Ⅲ/Ⅳ期在研药物
治疗途径 药物名称 类 型 临床分期 新陈代谢[13] Aramchol SCD-1抑制剂 Ⅲ MSDC-0602K 胰岛素增敏剂 Ⅲ Semaglutide GLP-1R激动剂 Ⅳ Dulaglutide GLP-1R 激动剂 Ⅳ Obeticholic acid FXR激动剂 Ⅲ Elafibranor PPARα/δ双重激动剂 Ⅲ Saroglitazar PPARα/δ双重激动剂 Ⅳ Lanifibranor PPAR激动剂 Ⅲ Erugliflozin SLGT-2抑制剂 Ⅳ Empagliflozin SLGT-2抑制剂 Ⅳ 炎症反应[14] Cenicriviroc CCR2/CCR5双拮抗剂 Ⅲ Belapectin GAL-3抑制剂 Ⅲ 细胞凋亡[15] Selonsertib ASK-1抑制剂 Ⅲ SCD-1：硬脂酰辅酶A去饱和酶1；GLP-1R：胰高血糖素样肽1受体；FXR：法尼醇X受体；PPAR：过氧化物酶体增殖物激活受体；SLGT-2：钠-葡萄糖协同转运蛋白2；CCR2/CCR5：C-C 趋化因子配体2型和5型；GAL-3：半乳糖凝集素-3；ASK-1：凋亡信号调节激酶1 
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表 2 MASLD中的乙酰化酶/去乙酰化酶
酶 MASLD中的表达 敲除细胞/动物 抑制/激活作用 SIRT2[41] 下调 加剧细胞脂肪堆积及HFD 诱导的小鼠肝脂肪变性和炎症反应 AGK2抑制SIRT2表达，阻断水飞蓟宾的抗炎作用 SIRT3[42−43] 下调 加剧HFD诱导的小鼠肝脂肪变性和炎症反应 蓝莓叶多酚激活AMPK/PGC-1α/SIRT3信号转导轴，缓解大鼠肝脂肪变性、氧化应激和炎症 SIRT6[44,48] 下调 加剧西方饮食诱导的小鼠MASH 薯蓣皂苷元激活SIRT6表达，缓解脂质积累和氧化应激 HDAC3[45] 上调 / 染料木黄酮抑制HDAC3表达，缓解HFHF饮食诱导的
大鼠MASHP300[46−47] 上调 / 单宁酸、3,4-二羟基甲苯抑制P300活性，
下调HepG2 脂肪生成相关基因表达并减弱脂质积累HFD：高脂肪饮食；AGK2：2-氰基-3-[5-(2,5-二氯苯基)-2-呋喃基]-N-5-喹啉基-2-丙烯酰胺；HFHF：高脂肪高果糖饮食；HepG2：人肝肿瘤细胞
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