脂肪自噬在非酒精性脂肪性肝病防治中的作用

肖智利; 卢晨霞; 周丹妮; 陈壮壮; 肖明中; 李晓东

doi:10.12449/JCH240725

脂肪自噬在非酒精性脂肪性肝病防治中的作用

DOI: 10.12449/JCH240725

肖智利¹,
卢晨霞^{2, 3, 4},
周丹妮^{2, 3, 4},
陈壮壮¹,
肖明中^{1, 2, 3, 4, , ,},
李晓东^{2, 3, 4}

1.
湖北中医药大学第一临床学院，武汉 430061
2.
湖北中医药大学附属医院肝病科，武汉 430061
3.
湖北省中医院肝病科，中医肝肾研究及应用湖北省重点实验室，武汉 430061
4.
湖北省中医药研究院，武汉 430074

基金项目:

国家自然科学基金面上项目 (82274352);

湖北省自然科学基金 (2020CFA023);

湖北省自然科学基金 (2023AFB426);

湖北省自然科学基金 (2023AFD129);

湖北省自然科学基金 (2023AFD178)

利益冲突声明：本文不存在任何利益冲突。

作者贡献声明：肖智利负责课题设计，收集与分析资料，撰写论文；卢晨霞、周丹妮参与分析资料，修改论文；陈壮壮参与收集资料；肖明中、李晓东负责拟定写作思路，指导撰写文章并最后定稿。

详细信息

通信作者:
肖明中， xmz0001@sohu.com （ORCID： 0000-0002-8432-703X）

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出版历程
- 收稿日期: 2023-11-23
- 录用日期: 2023-12-22
- 出版日期: 2024-07-25

Role of lipophagy in the prevention and treatment of nonalcoholic fatty liver disease

Zhili XIAO¹,
Chenxia LU^{2, 3, 4},
Danni ZHOU^{2, 3, 4},
Zhuangzhuang CHEN¹,
Mingzhong XIAO^{1, 2, 3, 4
, ,
,},
Xiaodong LI^{2, 3, 4}

1.
The First Clinical College of Hubei University of Chinese Medicine，Wuhan 430061，China
2.
Department of Hepatology，The Affiliated Hospital of Hubei University of Chinese Medicine，Wuhan 430061，China
3.
Department of Hepatology，Hubei Provincial Hospital of Traditional Chinese Medicine，Hubei Key Laboratory of Theoretical and Applied Research of Liver and Kidney in Traditional Chinese Medicine，Wuhan 430061，China
4.
Hubei Academy of Chinese Medicine，Wuhan 430074，China

Research funding:

General Project of National Natural Science Foundation of China (82274352);

Natural Science Foundation of Hubei Province (2020CFA023);

Natural Science Foundation of Hubei Province (2023AFB426);

Natural Science Foundation of Hubei Province (2023AFD129);

Natural Science Foundation of Hubei Province (2023AFD178)

More Information

Corresponding author: XIAO Mingzhong， xmz0001@sohu.com （ORCID： 0000-0002-8432-703X）

摘要

摘要: 目前非酒精性脂肪性肝病在国内外流行趋势不断上升，发病率逐年增加，已严重影响人类生命健康。脂肪自噬是分子伴侣介导的自噬，具有促进脂肪分解、维持肝细胞脂质稳态、缓解肝细胞脂肪变性等作用。脂肪自噬主要包括脂滴分解、脂滴自噬和脂肪酸β氧化三个过程，受关键基因、受体、酶调控。目前中药、西药及饮食运动等干预手段在脂肪自噬研究方面取得了重要进展，为非酒精性脂肪性肝病防治策略提供了新的视角。
- 非酒精性脂肪性肝病 /
- 自噬 /
- 治疗学
Abstract: Nowadays， the prevalence of nonalcoholic fatty liver disease （NAFLD） is constantly rising in China and globally， and its incidence rate is increasing year by year， which has seriously affected human life and health. Lipophagy is molecular chaperone-mediated autophagy and has the functions of promoting lipolysis， maintaining the lipid homeostasis of hepatocytes， and alleviating hepatocyte fatty degeneration. Lipophagy has three main processes of lipid droplet catabolism， lipid droplet autophagy， and fatty acid β-oxidation， which are regulated by key genes， receptors， and enzymes. Currently， important advances have been achieved for the intervention methods of traditional Chinese medicine， Western medicine， diet， and exercise in the research on lipophagy， which provides new perspectives for the prevention and treatment strategies for NAFLD.
- Non-alcoholic Fatty Liver Disease /
- Autophagy /
- Therapeutics

HTML全文

图 1 脂肪自噬过程

注： ATGL，脂肪甘油三酯脂肪酶。

Figure 1. The process of lipophagy

下载: 全尺寸图片幻灯片

图 2 NAFLD发展过程及其脂肪自噬的作用

Figure 2. The process of NAFLD development and the role of its lipophagy

下载: 全尺寸图片幻灯片

表 1 不同靶点对脂肪自噬的影响及在NAFLD中的可能作用机制

Table 1. Effect of different targets on lipophagy and possible mechanisms of action in NAFLD

靶点类型	靶点	影响	相关作用机制
基因	TFEB^［16］	增强	通过PGC-1α和PPARα调节参与脂质代谢相关基因
	TFE3^［17］	增强	激活PGC-lα介导的脂肪酸β氧化
	IRGM^［18］	增强	敲除IRGM抑制细胞中的自噬通量
	SRSF3^［19］	增强	SRSF3的缺失增加STX17的泛素化和降解，阻断自噬体和溶酶体的融合
	LXRα^［20］	减弱	转录激活microRNA let-7a-2和microRNA 34a基因，下调ATG4B和Rab-8B 抑制肝细胞中的自噬
	C9ORF72^［21］	减弱	激活Cdc42/N-WASP轴，抑制脂肪自噬
受体	ORP8^［22］	增强	ORP8与LC3/GABARAP相互作用，充当递送脂滴的受体
	SQSTM1/p62^［23］	增强	（1）作为非排他性脂肪自噬受体；（2）影响溶酶体中脂滴丰度
	CD36^［24-25］	减弱	与AMPK途径及ULK1/Beclin1的磷酸化有关
	P2RX7^［26］	增强	激活AMPK/ULK1途径
	mTORC1-Plin3^［27］	增强	mTORC1和脂滴包衣蛋白Plin3可作为对接蛋白，促进Plin3磷酸化
酶	ATGL	增强	促进脂肪分解过程
	STX11^［28］	减弱	（1）调节ATGL的空间分布；（2）削弱ATGL在肝细胞中的作用
	IFGGA2^［29］	增强	（1）IFGGA2与ATGL相互作用；（2）增强LC3B与脂滴的结合
	AMPK	增强	促进脂肪自噬过程
	SIRT3^［30］	增强	（1）激活AMPK和ULK1；（2）刺激LAMP2A-HSC70-PLN2复合物的形成
	SCD1^［31］	减弱	抑制肝细胞中SCD1表达可增强AMPK活性
	过氧化物酶体^［32］	减弱	促进RPTOR的乙酰化，激活mTOR活化抑制脂肪自噬

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表 2 不同干预手段基于脂肪自噬作用防治NAFLD的研究

Table 2. Different interventions against NAFLD based on the role of lipophagy

干预	相关靶点或通路	主要结论
西药
地高辛与阿培利司^［33］	尚未明确	通过脂肪自噬降低肝脂肪变性，减弱炎症和促纤维化基因的表达，抑制肝纤维化
二甲双胍^［34］	AMPK； AMPK-SIRT1轴	通过AMPK介导的氧化降低血浆游离脂肪酸，诱导自噬和自噬通量，AMPK-SIRT1轴诱导三四脯氨酸活化，以减少肝细胞坏死性凋亡；同时破坏肝细胞中脑内富含Ras同源物mRNA的稳定性来增加脂肪自噬
非诺贝特^［35］	CaMKKβ-AMPK-ULK1途径； TFEB；TFE3；mTOR	通过激活钙调磷酸酶和CaMKKβ-AMPK-ULK1途径，促进TFEB、TFE3去磷酸化和核易位，并以mTOR非依赖性方式减少肝脂肪堆积
生长分化因子11^［36］	尚未明确	上调细胞自噬，消除高脂导致的肝细胞脂质积累，并减少ROS，提升线粒体膜电位，从而改善NAFLD
培贝夫明^［37］	FGF21	FGF21参与了脂肪生成、糖摄取、β氧化、炎症和纤维化等过程的调节，可显著减少NASH患者的肝脂肪
p62激动剂^［38］	p62	通过N-degron促进脂肪自噬，治疗小鼠肝脂肪病和肥胖症
CAY10566^［31］	SCD1	增强的AMPK活性促进脂肪吞噬，显著减少肝脂肪变性和肝脂滴积聚
中药有效活性成分
川陈皮素^［39］	TFEB	通过TFEB介导的溶酶体生物发生和脂肪自噬来缓解肝脂肪变性，减少NOD样受体蛋白3炎症小体组装，调节体内外M1/M2巨噬细胞极化，从而减轻NAFLD
益母草苷^［40］	TFEB	促进TFEB介导的脂肪自噬以缓解NAFLD
益母草苷^［40］	尚未明确	通过脂肪自噬途径诱导肝脂肪清除
青钱柳提取物^［41］	尚未明确	通过脂肪自噬途径诱导肝脂肪清除
连翘脂素^［42］	钙调磷酸酶-TFEB轴	通过调节肝细胞中的钙调磷酸酶-TFEB轴来恢复脂肪自噬，并抑制脂质积累和炎症
柚皮苷^［43］	TFEB	促进自噬体和溶酶体的融合，恢复受损的自噬通量，并进一步诱导脂肪自噬，减轻肝脂肪变性
白藜芦醇苷^［44］	mTOR；TFEB	抑制mTOR信号传导并上调TFEB的表达和活性，恢复自噬通量改善NASH
芒柄花黄素^［45］	AMPK；TFEB	激活AMPK并促进TFEB的后续核易位，从而改善小鼠的肝脂肪变性
萝卜硫素^［46-47］	AMPK-mTOR-ULK1通路	Nrf2依赖性方式刺激脂肪自噬来增强脂滴降解，同时通过AMPK-mTOR-ULK1通路促进噬脂作用，改善肝细胞中脂滴的过度积累
人参皂苷化合物K^［48］	AMPK/ULK1途径；ATGL	与糖皮质激素受体结合，通过AMPK/ULK1途径激活脂肪自噬，同时促进糖皮质激素受体与ATGL启动子的结合，增加脂肪酶表达
和厚朴酚^［49］	SIRT3-AMPK-脂肪自噬轴	激活SIRT3-AMPK-脂肪自噬轴来改善肝细胞的脂毒性
槲皮素^［50-51］	AMPK	激活AMPK信号传导，促进脂肪自噬以产生线粒体中脂肪酸β氧化的底物；降低Perilipin 2水平，激活AMPK活性促进脂肪自噬，减轻肝脏脂肪的积累
甜叶菊和甜菊糖苷^［52］	PPARα	通过PPARα介导的脂肪自噬，减轻肝细胞中的肝脂肪变性
缬草及其环烯醚萜^［53］	mTORC1；Atg5	作为自噬增强剂来分解脂滴，通过抑制mTORC1活性诱导自噬，同时以Atg5依赖性方式减少脂质积累
饮食
高碳水化合物^［55］	ROS-AKT-Beclin1途径	肠道脂质积聚后，通过ROS-AKT-Beclin1途径激活肠上皮细胞中的脂肪自噬，减轻葡萄糖诱导的脂质积累
高磷饮食^［56］	AMPK	激活AMPK通路和上调Beclin1磷酸化水平，促进脂肪自噬来减少肝脂沉积
禁食^［57］	FGF21	诱导FGF21信号转导，通过组蛋白去甲基化酶激活肝脏脂肪自噬和脂质降解
饥饿后进食^［58］	尚未明确	激活肠道中的脂肪自噬
运动
跑步运动^［60］	FITM2、CIDEA和FSP27基因	降低脂滴生成以及脂滴扩张相关基因FITM2、CIDEA和FSP27的表达，促进LAMP1与脂滴的共定位，抑制异常脂滴膨胀和增强溶酶体噬脂作用，从而调节脂滴的生物发生和自噬以缓解NAFLD
游泳运动^［61］	AMPK/SIRT1	刺激AMPK/SIRT1激活肝脏的脂肪自噬，从而降低肝脂肪变性和胰岛素抵抗

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