Sorting Nexin 10 Mediates Metabolic Reprogramming of Macrophages in Atherosclerosis Through the Lyn-Dependent TFEB Signaling Pathway

doi:10.1161/CIRCRESAHA.119.315516

	Sorting Nexin 10 Mediates Metabolic Reprogramming of Macrophages in Atherosclerosis Through the Lyn-Dependent TFEB Signaling Pathway
	You, Yan 1,2,5; Bao, Wei-Lian 1,2; Zhang, Su-Lin 1,2; Li, Hai-Dong 1,2; Li, Hui 1,2; Dang, Wen-Zhen 1,2; Zou, Si-Li 4; Cao, Xin-Yue 1,2; Wang, Xu 1,2; Liu, Li-Xin 1,2
刊名	CIRCULATION RESEARCH
	2020-07-31
卷号	127 期号:4 页码:534-549
关键词	atherosclerosis foam cell lipid metabolism monocytes sorting nexin
ISSN号	0009-7330
DOI	10.1161/CIRCRESAHA.119.315516
通讯作者	Qu, Le-Feng(qulefeng@smmu.edu.cn) ; Zheng, Mingyue(myzheng@simm.ac.cn) ; Shen, Xiaoyan(shxiaoy@fudan.edu.cn)
英文摘要	Rationale: SNX10 (sorting nexin 10) has been reported to play a critical role in regulating macrophage function and lipid metabolism. Objective: To investigate the precise role of SNX10 in atherosclerotic diseases and the underlying mechanisms. Methods and Results: SNX10 expression was compared between human healthy vessels and carotid atherosclerotic plaques. Myeloid cell-specific SNX10 knockdown mice were crossed onto the APOE(-/-)(apolipoprotein E) background and atherogenesis (high-cholesterol diet-induced) was monitored for 16 weeks. We found that SNX10 expression was increased in atherosclerotic lesions of aortic specimens from humans and APOE(-/-)mice. Myeloid cell-specific SNX10 deficiency (Delta knockout [KO]) attenuated atherosclerosis progression in APOE(-/-)mice. The population of anti-inflammatory monocytes/macrophages was increased in the peripheral blood and atherosclerotic lesions of Delta KO mice. In vitro experiments showed that SNX10 deficiency-inhibited foam cell formation through interrupting the internalization of CD36, which requires the interaction of SNX10 and Lyn-AKT (protein kinase B). The reduced Lyn-AKT activation by SNX10 deficiency promoted the nuclear translocation of TFEB (transcription factor EB), thereby enhanced lysosomal biogenesis and LAL (lysosomal acid lipase) activity, resulting in an increase of free fatty acids to fuel mitochondrial fatty acid oxidation. This further promoted the reprogramming of macrophages and shifted toward the anti-inflammatory phenotype. Conclusions: Our data demonstrate for the first time that SNX10 plays a crucial role in diet-induced atherogenesis via the previously unknown link between the Lyn-Akt-TFEB signaling pathway and macrophage reprogramming, suggest that SNX10 may be a potentially promising therapeutic target for atherosclerosis treatment.
资助项目	National Natural Science Foundation of China[81773744] ; National Natural Science Foundation of China[81573441] ; National Natural Science Foundation of China[81971488] ; Personalized Medicines-Molecular Signature-based Drug Discovery and Development, Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12020368] ; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences[SIMM1903KF-05] ; Fudan-SIMM Joint Research Fund[FU-SIMM20183002]
WOS关键词	CELL ; POLARIZATION ; ACTIVATION ; IMMUNOMETABOLISM ; DISRUPTION ; RESPONSES ; CD36 ; AXIS
WOS研究方向	Cardiovascular System & Cardiology ; Hematology
语种	英语
出版者	LIPPINCOTT WILLIAMS & WILKINS
WOS记录号	WOS:000559798700009
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/292295]
专题	中国科学院上海药物研究所
通讯作者	Qu, Le-Feng; Zheng, Mingyue; Shen, Xiaoyan
作者单位	1.Fudan Univ, Dept Pharmacol, Sch Pharm, Minist Educ, Shanghai, Peoples R China 2.Fudan Univ, Sch Pharm, Key Lab Smart Drug Delivery, Minist Educ, Shanghai, Peoples R China 3.Chinese Acad Sci, Drug Discovery & Design Ctr, Shanghai Inst Mat Med, State Key Lab Drug Res, Beijing, Peoples R China 4.Second Mil Med Univ, Changzheng Hosp, Dept Vasc & Endovasc Surg, 415 Fengyang Rd, Shanghai 200003, Peoples R China 5.Natl Inst Allergy & Infect, NIH, Rockville, MD USA
推荐引用方式 GB/T 7714	You, Yan,Bao, Wei-Lian,Zhang, Su-Lin,et al. Sorting Nexin 10 Mediates Metabolic Reprogramming of Macrophages in Atherosclerosis Through the Lyn-Dependent TFEB Signaling Pathway[J]. CIRCULATION RESEARCH,2020,127(4):534-549.
APA	You, Yan.,Bao, Wei-Lian.,Zhang, Su-Lin.,Li, Hai-Dong.,Li, Hui.,...&Shen, Xiaoyan.(2020).Sorting Nexin 10 Mediates Metabolic Reprogramming of Macrophages in Atherosclerosis Through the Lyn-Dependent TFEB Signaling Pathway.CIRCULATION RESEARCH,127(4),534-549.
MLA	You, Yan,et al."Sorting Nexin 10 Mediates Metabolic Reprogramming of Macrophages in Atherosclerosis Through the Lyn-Dependent TFEB Signaling Pathway".CIRCULATION RESEARCH 127.4(2020):534-549.