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

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, responsib...

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Autores principales: Li, Luxiao, Zhong, Shanshan, Li, Rui, Liang, Ningning, Zhang, Lili, Xia, Shen, Xu, Xiaodong, Chen, Xin, Chen, Shiting, Tao, Yongzhen, Yin, Huiyong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Clinical Investigation 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9057588/
https://www.ncbi.nlm.nih.gov/pubmed/35393951
http://dx.doi.org/10.1172/jci.insight.155869
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author Li, Luxiao
Zhong, Shanshan
Li, Rui
Liang, Ningning
Zhang, Lili
Xia, Shen
Xu, Xiaodong
Chen, Xin
Chen, Shiting
Tao, Yongzhen
Yin, Huiyong
author_facet Li, Luxiao
Zhong, Shanshan
Li, Rui
Liang, Ningning
Zhang, Lili
Xia, Shen
Xu, Xiaodong
Chen, Xin
Chen, Shiting
Tao, Yongzhen
Yin, Huiyong
author_sort Li, Luxiao
collection PubMed
description 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(ADP-ribose) polymerase 1 (PARP1) and attenuated PARP1 nuclear translocation to downregulate poly(ADP-ribosyl)ation of liver X receptor α (LXRα), 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 LXRα 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 LXRα poly(ADP-ribosyl)ation. Our study uncovered a key role of ALDH2 in HDL biogenesis through the LXRα/PARP1/ABCA1 axis, highlighting a potential therapeutic strategy in CVD.
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spelling pubmed-90575882022-05-04 Aldehyde dehydrogenase 2 and PARP1 interaction modulates hepatic HDL biogenesis by LXRα-mediated ABCA1 expression Li, Luxiao Zhong, Shanshan Li, Rui Liang, Ningning Zhang, Lili Xia, Shen Xu, Xiaodong Chen, Xin Chen, Shiting Tao, Yongzhen Yin, Huiyong JCI Insight Research Article 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(ADP-ribose) polymerase 1 (PARP1) and attenuated PARP1 nuclear translocation to downregulate poly(ADP-ribosyl)ation of liver X receptor α (LXRα), 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 LXRα 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 LXRα poly(ADP-ribosyl)ation. Our study uncovered a key role of ALDH2 in HDL biogenesis through the LXRα/PARP1/ABCA1 axis, highlighting a potential therapeutic strategy in CVD. American Society for Clinical Investigation 2022-04-08 /pmc/articles/PMC9057588/ /pubmed/35393951 http://dx.doi.org/10.1172/jci.insight.155869 Text en © 2022 Li et al. https://creativecommons.org/licenses/by/4.0/This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Research Article
Li, Luxiao
Zhong, Shanshan
Li, Rui
Liang, Ningning
Zhang, Lili
Xia, Shen
Xu, Xiaodong
Chen, Xin
Chen, Shiting
Tao, Yongzhen
Yin, Huiyong
Aldehyde dehydrogenase 2 and PARP1 interaction modulates hepatic HDL biogenesis by LXRα-mediated ABCA1 expression
title Aldehyde dehydrogenase 2 and PARP1 interaction modulates hepatic HDL biogenesis by LXRα-mediated ABCA1 expression
title_full Aldehyde dehydrogenase 2 and PARP1 interaction modulates hepatic HDL biogenesis by LXRα-mediated ABCA1 expression
title_fullStr Aldehyde dehydrogenase 2 and PARP1 interaction modulates hepatic HDL biogenesis by LXRα-mediated ABCA1 expression
title_full_unstemmed Aldehyde dehydrogenase 2 and PARP1 interaction modulates hepatic HDL biogenesis by LXRα-mediated ABCA1 expression
title_short Aldehyde dehydrogenase 2 and PARP1 interaction modulates hepatic HDL biogenesis by LXRα-mediated ABCA1 expression
title_sort aldehyde dehydrogenase 2 and parp1 interaction modulates hepatic hdl biogenesis by lxrα-mediated abca1 expression
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9057588/
https://www.ncbi.nlm.nih.gov/pubmed/35393951
http://dx.doi.org/10.1172/jci.insight.155869
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