Aldehyde dehydrogenase 2 and PARP1 interaction modulates hepatic HDL biogenesis by LXR alpha-mediated ABCA1 expression

doi:10.1172/jci.insight.155869

	Aldehyde dehydrogenase 2 and PARP1 interaction modulates hepatic HDL biogenesis by LXR alpha-mediated ABCA1 expression
	Li, Luxiao 1; Zhong, Shanshan 1; Li, Rui2 ; Liang, Ningning 1; Zhang, Lili 1; Xia, Shen2 ; Xu, Xiaodong 1; Chen, Xin 1; Chen, Shiting 1; Tao, Yongzhen 1; Yin, Huiyong1,2,3
	2022-04-08
发表期刊	JCI INSIGHT
EISSN	2379-3708
卷号	7 期号:7
发表状态	已发表
DOI	10.1172/jci.insight.155869
摘要	HDL cholesterol (HDL-C) predicts risk of cardiovascular disease (CVD), but the factors regulating HDL are incompletely understood. Emerging data link CVD risk to decreased HDL-C in 8% of the world population and 40% of East Asians who carry an SNP of aldehyde dehydrogenase 2 (ALDH2) rs671, responsible for alcohol flushing syndrome; however, the underlying mechanisms remain unknown. We found significantly decreased HDL-C with increased hepatosteatosis in ALDH2-KO (AKO), ALDH2/LDLR-double KO (ALKO), and ALDH2 rs671-knock-in (KI) mice after consumption of a Western diet. Metabolomics identified ADP-ribose as the most significantly increased metabolites in the ALKO mouse liver. Moreover, ALDH2 interacted with poly(ADPribose) polymerase 1 (PARP1) and attenuated PARP1 nuclear translocation to downregulate poly(ADP-ribosyl)ation of liver X receptor alpha (LXR alpha), leading to an upregulation of ATP-binding cassette transporter A1 (ABCA1) and HDL biogenesis. Conversely, AKO or ALKO mice exhibited lower HDL-C with ABCA1 downregulation due to increased nuclear PARP1 and upregulation of LXR alpha poly(ADP-ribosyl)ation. Consistently, PARP1 inhibition rescued ALDH2 deficiency-induced fatty liver and elevated HDL-C in AKO mice. Interestingly, KI mouse or human liver tissues showed ABCA1 downregulation with increased nuclear PARP1 and LXR alpha poly(ADP-ribosyl)ation. Our study uncovered a key role of ALDH2 in HDL biogenesis through the LXR alpha/PARP1/ABCA1 axis, highlighting a potential therapeutic strategy in CVD.
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收录类别	SCI ; SCIE
语种	英语
资助项目	National Natural Science Foundation of China[32030053,91857112,32150710522] ; National Key R&D Program of China[2018YFA0800301]
WOS研究方向	Research & Experimental Medicine
WOS类目	Medicine, Research & Experimental
WOS记录号	WOS:000785990200001
出版者	AMER SOC CLINICAL INVESTIGATION INC
引用统计
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/180881
专题	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, Univ Chinese Acad Sci UCAS, Shanghai Inst Nutr & Hlth SINH, CAS Key Lab Nutr Metab & Food Safety, Shanghai, Peoples R China 2.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai, Peoples R China 3.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	Li, Luxiao,Zhong, Shanshan,Li, Rui,et al. Aldehyde dehydrogenase 2 and PARP1 interaction modulates hepatic HDL biogenesis by LXR alpha-mediated ABCA1 expression[J]. JCI INSIGHT,2022,7(7).
APA	Li, Luxiao.,Zhong, Shanshan.,Li, Rui.,Liang, Ningning.,Zhang, Lili.,...&Yin, Huiyong.(2022).Aldehyde dehydrogenase 2 and PARP1 interaction modulates hepatic HDL biogenesis by LXR alpha-mediated ABCA1 expression.JCI INSIGHT,7(7).
MLA	Li, Luxiao,et al."Aldehyde dehydrogenase 2 and PARP1 interaction modulates hepatic HDL biogenesis by LXR alpha-mediated ABCA1 expression".JCI INSIGHT 7.7(2022).