Acetaldehyde dehydrogenase 2 interactions with LDLR and AMPK regulate foam cell formation
Shanshan Zhong, … , Yun-Cheng Wu, Huiyong Yin
Shanshan Zhong, … , Yun-Cheng Wu, Huiyong Yin
Published October 30, 2018
Citation Information: J Clin Invest. 2019;129(1):252-267. https://doi.org/10.1172/JCI122064.
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Research Article Cell biology Metabolism

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.

Authors

Shanshan Zhong, Luxiao Li, Yu-Lei Zhang, Lili Zhang, Jianhong Lu, Shuyuan Guo, Ningning Liang, Jing Ge, Mingjiang Zhu, Yongzhen Tao, Yun-Cheng Wu, Huiyong Yin

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Figure 5

AMPK phosphorylates ALDH2 and promotes ALDH2 translocation in the absence of LDLR or ALDH2 rs671 mutant.

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AMPK phosphorylates ALDH2 and promotes ALDH2 translocation in the absenc...
(A) AMPK activation promotes ALDH2 nuclear translocation in LDLR-KO BMDMs by cellular fractionation (LKO; n = 3). (B) ALDH2 rs671 mutant increases the translocation of ALDH2 in 293T cells (n = 3). (C) AMPK activation leads to ALDH2 nuclear translocation, whereas inhibition of AMPK blocks nuclear translocation of ALDH2. Scale bars: 5 μm. (D) Quantification of ALDH2 in the nucleus (n = 5). (E) LDLR blocks the translocation of ALDH2 even AMPK activation. Scale bars: 5 μm. Quantification shown in F (n = 5). (G) AMPK activation leads to a dose-dependent increase of ALDH2 phosphorylation in the absence of LDLR in LKO macrophages by SuperSep Phos-tag SDS-PAGE. Statistical comparisons were made using ANOVA. All data are mean ± SD. *P < 0.05, **P < 0.01, ***P < 0.001.