ArticleJournal of hepatology2021
Alcohol-induced Hsp90 acetylation is a novel driver of liver sinusoidal endothelial dysfunction and alcohol-related liver disease.
Article in Journal of hepatology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 41 papers.
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Who cites it
41 citing papers in PubMed, 67 citations in OpenAlex.
- An experimental study on the role of naloxone in facilitating alcohol metabolism in acute alcohol intoxication rats.Future science OA · 2026Article
- Platelet-derived S100A9 contributes to endotheliopathy in alcohol-associated hepatitis.JCI insight · 2026Article
- Liver sinusoidal endothelial cells in liver diseases and hepatocellular carcinoma: molecular mechanisms, physiology, and therapies.Molecular biomedicine · 2026Review
- The Scavenger Function of LSECs, a Regulator of Liver Diseases.Current issues in molecular biology · 2026Review
- Liver sinusoidal endothelial cell fenestrations in metabolic liver disease: from molecular mechanisms to therapeutic perspectives.Cell communication and signaling : CCS · 2026Review
- Gut-liver axis molecular mechanisms in alcohol-associated liver disease.Alcohol (Fayetteville, N.Y.) · 2026Review
- HMGB1-mediated enhancement of glycolysis activates hepatic stellate cells by inhibiting ferroptosis in alcoholic hepatic fibrosis.Stem cell research & therapy · 2026Article
- [Histone deacetylases and alcohol-related liver disease].Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences · 2026Review
- MSCs-derived CRABP2 regulates Treg/CXCL1 to ameliorate alcohol-induced liver injury.Cell communication and signaling : CCS · 2026Article
- Novel Vascularized Human Liver Organoids for Modeling Alcohol-Induced Liver Injury and Developing Hepatoprotective Therapy.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Identification of Wnt/β-catenin- and immune-related genes in hepatic ischemia-reperfusion injury using bulk transcriptomics, single-cell RNA sequencing, and a murine model.Frontiers in immunology · 2026Article
- Mechanistic insights into hepatic cell type-specific contributions to acetaminophen-induced acute liver injury.World journal of gastroenterology · 2025Review
- The Mechanism and Potential Therapeutic Strategies of Vascular Aging.Aging medicine (Milton (N.S.W)) · 2025Review
- Article
- Mechanism of Reactive Oxygen/Nitrogen Species in Liver Ischemia-Reperfusion Injury and Preventive Effect of Chinese Medicine.Chinese journal of integrative medicine · 2025Review
- IRF4 Knockdown Inhibits the Chronic Rhinosinusitis Without Nasal Polyps Development by Regulating NLRP3/Caspase-1/GSDMD-Mediated Pyroptosis.Biochemical genetics · 2025Article
- Deciphering the cell type-specific and zonal distribution of drug-metabolizing enzymes, transporters, and transcription factors in livers of mice using single-cell transcriptomics.Drug metabolism and disposition: the biological fate of chemicals · 2025Article
- Efficient generation of liver sinusoidal endothelial-like cells secreting coagulation factor VIII from human induced pluripotent stem cells.Molecular therapy. Methods & clinical development · 2024Article
- Inhibition of Hsp90 K284 Acetylation Aalleviates Cardiac Injury After Ischemia-Reperfusion Injury.Journal of cardiovascular translational research · 2024Article
- Cell-to-cell and organ-to-organ crosstalk in the pathogenesis of alcohol-associated liver disease.eGastroenterology · 2024Article
Corrections and comments
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Authors and funding
9 authors at 2 institutions in 2 countries.
Funding
Abstract
BACKGROUND &
aimsLiver sinusoidal endothelial cell (LSEC) dysfunction has been reported in alcohol-related liver disease, yet it is not known whether LSECs metabolize alcohol. Thus, we investigated this, as well as the mechanisms of alcohol-induced LSEC dysfunction and a potential therapeutic approach for alcohol-induced liver injury.
methodsPrimary human, rat and mouse LSECs were used. Histone deacetylase 6 (HDAC6) was overexpressed specifically in liver ECs via adeno-associated virus (AAV)-mediated gene delivery to decrease heat shock protein 90 (Hsp90) acetylation in ethanol-fed mice.
resultsLSECs 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 endothelial nitric oxide synthase (eNOS) leading to a decrease in nitric oxide (NO) production. A non-acetylation mutant of Hsp90 increased its interaction with eNOS and NO production, whereas a hyperacetylation mutant decreased NO production. These results indicate that Hsp90 acetylation is responsible for decreases in its interaction with eNOS and eNOS-derived NO production. AAV8-driven HDAC6 overexpression specifically in liver ECs deacetylated Hsp90, restored Hsp90's interaction with eNOS and ameliorated alcohol-induced liver injury in mice.
conclusionRestoring 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. LAY SUMMARY: Alcohol metabolism in liver sinusoidal endothelial cells (LSECs) and the mechanism of alcohol-induced LSEC dysfunction are largely unknown. Herein, we demonstrate that LSECs can metabolize alcohol. We also uncover a mechanism by which alcohol induces LSEC dysfunction and liver injury, and we identify a potential therapeutic strategy to prevent this.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.