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

ABSTRACT: Acetaldehyde dehydrogenase 2 (ALDH2) is a mitochondrial 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.

SUBMITTER: Zhong S

PROVIDER: S-EPMC6307968 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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

Zhong Shanshan S Li Luxiao L Zhang Yu-Lei YL Zhang Lili L Lu Jianhong J Guo Shuyuan S Liang Ningning N Ge Jing J Zhu Mingjiang M Tao Yongzhen Y Wu Yun-Cheng YC Yin Huiyong H

The Journal of clinical investigation 20181203 1

Acetaldehyde dehydrogenase 2 (ALDH2) is a mitochondrial 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 atherosc ...[more]

PMID: 30375985

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

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

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