| Aldehyde dehydrogenase 2 and PARP1 interaction modulates hepatic HDL biogenesis by LXR alpha-mediated ABCA1 expression |
| Author |
Li, LX; Zhong, SS; Li, R; Liang, NN; Zhang, LL; Xia, S; Xu, XD; Chen, X; Chen, ST; Tao, YZ; Yin, HY |
| Journal |
JCI INSIGHT |
| Pub Year |
2022 |
| Type |
Article |
| Abstract |
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. |
| Issue |
7 |
| Volume |
7 |
