{"doi":"10.1101/2020.08.25.267096","title":"Alcohol-induced Hsp90 acetylation is a novel driver of liver sinusoidal endothelial dysfunction and alcoholic liver disease","abstract":"Abstract Background It is unknown whether liver sinusoidal endothelial cells (LSECs) metabolize alcohol. Chronic alcohol consumption decreases endothelial nitric oxide synthase (eNOS)-derived NO production typical of LSEC dysfunction. Heat shock protein 90 (Hsp90) interacts with eNOS to increase its activity. Cytochrome P450 2E1 (CYP2E1) is a key enzyme in alcohol metabolism and facilitates protein acetylation via acetyl-CoA, but its expression in LSECs is unknown. This study investigates alcohol metabolism by LSECs, the mechanism of alcohol-induced LSEC dysfunction and a potential therapeutic approach for alcohol-induced liver injury. Methods Primary human, rat and mouse LSECs were used. Histone deacetylase 6 (HDAC6) was overexpressed specifically in liver ECs using an adeno-associated virus (AAV)-mediated gene delivery system to decrease Hsp90 acetylation in ethanol fed mice. Results LSECs expressed CYP2E1 and alcohol dehydrogenase 1 (ADH1) and metabolized alcohol. Ethanol induced CYP2E1 in LSECs, but not ADH1. Alcohol metabolism by CYP2E1 increased Hsp90 acetylation and decreased its interaction with eNOS along with a decrease in NO production. A non-acetylation mutant of Hsp90 increased its interaction with eNOS and NO production, whereas a hyper-acetylation mutant decreased NO production, compared with wildtype Hsp90. These results indicate that Hsp90 acetylation is responsible for decreases in its interaction with eNOS and eNOS-derived NO production. Adeno-associated virus 8 (AAV8)-driven HDAC6 overexpression specifically in liver ECs deacetylated Hsp90, restored Hsp90’s interaction with eNOS and ameliorated alcohol-induced liver injury in mice. Conclusion Restoring LSEC function is important for ameliorating alcohol-induced liver injury. To this end, blocking acetylation of Hsp90 specifically in LSECs via AAV-mediated gene delivery has the potential to be a new therapeutic strategy.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2020,"id":127239,"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":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9646,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":576558,"name":"Panjamaporn Sungwung","orcid":null,"position":1,"is_corresponding":false},{"id":554990,"name":"Yirang Jung","orcid":null,"position":2,"is_corresponding":false},{"id":437272,"name":"Reiichiro Kondo","orcid":"0000-0002-2769-7392","position":3,"is_corresponding":false},{"id":553968,"name":"Matthew J. McConnell","orcid":"0000-0002-8522-0381","position":4,"is_corresponding":false},{"id":554991,"name":"Teruo Utsumi","orcid":null,"position":5,"is_corresponding":false},{"id":328610,"name":"William C. Sessa","orcid":"0000-0001-5759-1938","position":6,"is_corresponding":false},{"id":437273,"name":"Yasuko Iwakiri","orcid":"0000-0001-8032-5654","position":7,"is_corresponding":false},{"id":553967,"name":"Yilin Yang","orcid":"0000-0001-7738-4805","position":0,"is_corresponding":true}],"reference_count":53,"raw_metadata":null,"created_at":"2026-07-18T23:15:30.930746Z","pmid":null,"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":[]}