Acetaldehyde dehydrogenase 2 interactions with LDLR and AMPK regulate foam cell formation

doi:10.1172/JCI122064

	Acetaldehyde dehydrogenase 2 interactions with LDLR and AMPK regulate foam cell formation
	Zhong, Shanshan 1,2; Li, Luxiao1,2,3 ; Zhang, Yu-Lei 4; Zhang, Lili 1,2; Lu, Jianhong 1,2; Guo, Shuyuan1,2,3 ; Liang, Ningning 1,2; Ge, Jing 1,2; Zhu, Mingjiang 1; Tao, Yongzhen 1; Wu, Yun-Cheng 4; Yin, Huiyong1,2,3,5
	2019-01-02
发表期刊	JOURNAL OF CLINICAL INVESTIGATION
ISSN	0021-9738
卷号	129 期号:1 页码:252-267
发表状态	已发表
DOI	10.1172/JCI122064
摘要	Acetaldehyde dehydrogenase 2 (ALDH2) is a mitochondria, enzyme detoxifying acetaldehyde and endogenous lipid aldehydes; previous studies suggest a protective role of ALDH2 against cardiovascular disease (CVD). Around 40% of East Asians carrying the single nucleotide polymorphism (SNP) ALDH2 rs671 have an increased incidence of CVD. However, the role of ALDH2 in CVD beyond alcohol consumption remains poorly defined. Here we report that ALDH2/LDLR double knockout (DKO) mice have decreased atherosclerosis compared with LDLR-KO mice, whereas ALDH2/APOE-DKO mice have increased atherosclerosis, suggesting an unexpected interaction of ALDH2 with LDLR. Further studies demonstrate that in the absence of LDLR, AMPK phosphorylates ALDH2 at threonine 356 and enables its nuclear translocation. Nuclear ALDH2 interacts with HDAC3 and represses transcription of a lysosomal proton pump protein ATP6V0E2, critical for maintaining lysosomal function, autophagy, and degradation of oxidized low-density lipid protein. Interestingly, an interaction of cytosolic LDLR C-terminus with AMPK blocks ALDH2 phosphorylation and subsequent nuclear translocation, whereas ALDH2 rs671 mutant in human macrophages attenuates this interaction, which releases ALDH2 to the nucleus to suppress ATP6V0E2 expression, resulting in increased foam cells due to impaired lysosomal function. Our studies reveal a novel role of ALDH2 and LDLR in atherosclerosis and provide a molecular mechanism by which ALDH2 rs671 SNP increases CVD.
收录类别	SCI ; SCIE
语种	英语
资助项目	Chinese Academy of Sciences[ZDBS-SSW-DQC-02]
WOS研究方向	Research & Experimental Medicine
WOS类目	Medicine, Research & Experimental
WOS记录号	WOS:000454717400033
出版者	AMER SOC CLINICAL INVESTIGATION INC
WOS关键词	MITOCHONDRIAL ALDEHYDE DEHYDROGENASE ; MYOCARDIAL-INFARCTION ; V-ATPASE ; ALDH2 ; ACTIVATION ; AUTOPHAGY ; RECEPTOR ; MICE ; HYPERCHOLESTEROLEMIA ; ATHEROSCLEROSIS
原始文献类型	Article
引用统计
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/30055
专题	生命科学与技术学院_硕士生生命科学与技术学院_特聘教授组_尹慧勇组生命科学与技术学院_博士生
通讯作者	Yin, Huiyong
作者单位	1.Chinese Acad Sci, SIBS, Shanghai Inst Nutr & Hlth, CAS Key Lab Nutr Metab & Food Safety, Shanghai, Peoples R China 2.Chinese Acad Sci, Univ Chinese Acad Sci, Beijing, Peoples R China 3.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai, Peoples R China 4.Shanghai Jiao Tong Univ, Shanghai Gen Hosp, Dept Neurol, Sch Med, Shanghai, Peoples R China 5.Minist Hlth, Key Lab Food Safety Risk Assessment, Beijing, Peoples R China
通讯作者单位	生命科学与技术学院
推荐引用方式 GB/T 7714	Zhong, Shanshan,Li, Luxiao,Zhang, Yu-Lei,et al. Acetaldehyde dehydrogenase 2 interactions with LDLR and AMPK regulate foam cell formation[J]. JOURNAL OF CLINICAL INVESTIGATION,2019,129(1):252-267.
APA	Zhong, Shanshan.,Li, Luxiao.,Zhang, Yu-Lei.,Zhang, Lili.,Lu, Jianhong.,...&Yin, Huiyong.(2019).Acetaldehyde dehydrogenase 2 interactions with LDLR and AMPK regulate foam cell formation.JOURNAL OF CLINICAL INVESTIGATION,129(1),252-267.
MLA	Zhong, Shanshan,et al."Acetaldehyde dehydrogenase 2 interactions with LDLR and AMPK regulate foam cell formation".JOURNAL OF CLINICAL INVESTIGATION 129.1(2019):252-267.