| First Author | Li L | Year | 2022 |
| Journal | JCI Insight | Volume | 7 |
| Issue | 7 | PubMed ID | 35393951 |
| Mgi Jnum | J:378815 | Mgi Id | MGI:7275721 |
| Doi | 10.1172/jci.insight.155869 | Citation | Li L, et al. (2022) Aldehyde dehydrogenase 2 and PARP1 interaction modulates hepatic HDL biogenesis by LXRalpha-mediated ABCA1 expression. JCI Insight 7(7):e155869 |
| abstractText | 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 alpha (LXRalpha), 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 LXRalpha 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 LXRalpha poly(ADP-ribosyl)ation. Our study uncovered a key role of ALDH2 in HDL biogenesis through the LXRalpha/PARP1/ABCA1 axis, highlighting a potential therapeutic strategy in CVD. |
