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

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 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.

Portal hypertension in cirrhosis: Pathophysiological mechanisms and therapy

“…Heat shock protein 90 (Hsp90) activates eNOS, leading to NO production (18). Recently, we reported a mechanism of alcohol-driven LSEC dysfunction (19). In this study, we showed that LSECs can metabolize ethanol and that ethanol can increase Hsp90 acetylation through enhanced production of acetyl-CoA, a substrate for protein acetylation, by the action of alcohol dehydrogenase1 (ADH1) and cytochrome P450 2E1 (CYP2E1) (19).…”

“…Further, acetylation of Hsp90 decreases its interaction with eNOS, decreasing production of eNOS-derived NO, while a de-acetylation mutant of Hsp90 increases an interaction with eNOS, leading to NO production. Overexpression of histone deacetylase 6 (HDAC6), an Hsp90 specific de-acetylase enzyme (20), in liver endothelial cells in mice increased the association of Hsp90 with eNOS and increased NO production, resulting in ameliorating alcohol-induced liver injury (19). These observations indicate that LSEC dysfunction can be treated in an ethiology-specific manner.…”

“…Recently, we reported a mechanism of alcohol-driven LSEC dysfunction (19). In this study, we showed that LSECs can metabolize ethanol and that ethanol can increase Hsp90 acetylation through enhanced production of acetyl-CoA, a substrate for protein acetylation, by the action of alcohol dehydrogenase1 (ADH1) and cytochrome P450 2E1 (CYP2E1) (19). Further, acetylation of Hsp90 decreases its interaction with eNOS, decreasing production of eNOS-derived NO, while a de-acetylation mutant of Hsp90 increases an interaction with eNOS, leading to NO production.…”

Metabolic Toxification of 1,2-Unsaturated Pyrrolizidine Alkaloids Causes Human Hepatic Sinusoidal Obstruction Syndrome: The Update

“…The metabolism of unsaturated PAs occurs in the hepatocytes [ 172 ] and not in the LSECs that do not express active CYP isoforms like CYP 3A4 [ 185 ], essential for PA degradation ( Table 4 ) [ 172 ]. Instead, LSECs merely express the CYP 1B1 and CYP 2E1 isoforms [ 185 , 186 , 187 ], both lack relevance for enzymatic PA degradation [ 172 ]. LSECs with their CYP 2E1 metabolize ethanol [ 187 ], and CYP 1B1 impacts the angiogenic and inflammatory properties of LSECs [ 185 ].…”

Serum Amyloid A promotes Acetaminophen-induced liver injury by damaging sinusoidal endothelial cell and exacerbating platelet aggregation in liver

“…However, the mechanism of APAP-induced sinusoidal endothelial cell injury is still unclear. It has recently been reported that LSECs expressed CYP2E1, which is a key enzyme for metabolizing APAP into toxic intermediate NAQPI [18]. It suggests that APAP may directly induce sinusoid endothelial cell damage.…”