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bioRxiv · 10.1101/2020.08.25.267096

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

Yang, Y.·Sungwung, P.·Jung, Y.·Kondo, R.·McConnell, M.·Utsumi, T.·Sessa, W.·Iwakiri, Y.
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Abstract

BackgroundIt 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. MethodsPrimary 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. 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 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 Hsp90s 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.

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Yang, Y., Sungwung, P., Jung, Y., Kondo, R., McConnell, M., Utsumi, T., Sessa, W., Iwakiri, Y.. 2020-08-25. Alcohol-induced Hsp90 acetylation is a novel driver of liver sinusoidal endothelial dysfunction and alcoholic liver disease. https://doi.org/10.1101/2020.08.25.267096

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