{"doi":"10.1172/jci.insight.155869","title":"Aldehyde dehydrogenase 2 and PARP1 interaction modulates hepatic HDL biogenesis by LXRα-mediated ABCA1 expression","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(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.","journal":"JCI Insight","year":2022,"id":270072,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":14,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9597,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":933764,"name":"Shanshan Zhong","orcid":"0000-0003-3447-8398","position":1,"is_corresponding":false},{"id":933765,"name":"Rui Li","orcid":"0000-0002-3199-287X","position":2,"is_corresponding":false},{"id":631892,"name":"Ningning Liang","orcid":"0000-0003-1439-7929","position":3,"is_corresponding":false},{"id":538101,"name":"Lili Zhang","orcid":"0000-0002-1625-7877","position":4,"is_corresponding":false},{"id":933766,"name":"Xia Shen","orcid":"0000-0002-3711-2028","position":5,"is_corresponding":false},{"id":933767,"name":"Xiaodong Xu","orcid":"0000-0002-9580-9835","position":6,"is_corresponding":false},{"id":933768,"name":"Xin Chen","orcid":"0000-0001-7234-8135","position":7,"is_corresponding":false},{"id":933769,"name":"Shiting Chen","orcid":"0000-0003-2104-1779","position":8,"is_corresponding":false},{"id":933770,"name":"Yongzhen Tao","orcid":"0000-0003-1710-5346","position":9,"is_corresponding":false},{"id":631895,"name":"Huiyong Yin","orcid":"0000-0001-7049-1560","position":10,"is_corresponding":false},{"id":934393,"name":"Luxiao Li","orcid":null,"position":0,"is_corresponding":true}],"reference_count":60,"raw_metadata":null,"created_at":"2026-07-19T00:27:26.772098Z","pmid":"35393951","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}