Alcohol-induced Hsp90 acetylation is a novel driver of liver sinusoidal endothelial dysfunction and alcohol-related liver disease.

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  • Additional Information
    • Source:
      Publisher: Elsevier Country of Publication: Netherlands NLM ID: 8503886 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1600-0641 (Electronic) Linking ISSN: 01688278 NLM ISO Abbreviation: J Hepatol Subsets: MEDLINE
    • Publication Information:
      Publication: 2001- : Amsterdam : Elsevier
      Original Publication: Copehnagen : Munksgaard International Publishers, [c1984-
    • Subject Terms:
      Acetylation/*drug effects ; Liver Diseases, Alcoholic/*genetics; Adult ; Alcohol Drinking/adverse effects ; Alcohol Drinking/physiopathology ; Analysis of Variance ; Animals ; Endothelial Cells/drug effects ; Endothelial Cells/enzymology ; HSP90 Heat-Shock Proteins ; Humans ; Liver Diseases, Alcoholic/etiology ; Mice ; Rats
    • Abstract:
      Background & Aims: Liver 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.
      Methods: Primary 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.
      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 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.
      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.
      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.
      Competing Interests: Conflict of interest The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details.
      (Copyright © 2021 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)
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    • Grant Information:
      R01 AA025342 United States AA NIAAA NIH HHS; UL1 TR001863 United States TR NCATS NIH HHS; R01 DK117597 United States DK NIDDK NIH HHS; R21 AA023599 United States AA NIAAA NIH HHS; KL2 TR001862 United States TR NCATS NIH HHS; P30 DK034989 United States DK NIDDK NIH HHS
    • Contributed Indexing:
      Keywords: adeno-associated virus (AAV); alcohol dehydrogenase 1 (ADH1); cytochrome P450 2E1 (CYP2E1); endothelial nitric oxide synthase (eNOS); gene delivery; histone deacetylase 6 (HDAC6)
    • Accession Number:
      0 (HSP90 Heat-Shock Proteins)
    • Publication Date:
      Date Created: 20210306 Date Completed: 20220207 Latest Revision: 20220802
    • Publication Date:
      20231215
    • Accession Number:
      PMC8292196
    • Accession Number:
      10.1016/j.jhep.2021.02.028
    • Accession Number:
      33675874