Recent preclinical studies further suggest that FAEE plays a major role in the acute damaging effects of alcohol binge drinking and extends findings from the pancreas to the liver (108). Using multiple lines of genetically modified mice, Park and collaborators (108) showed that, compared to wild-type control animals, acute liver injury was worsened in mice lacking ADH1. As expected, these mice exhibited markedly increased BAC after receiving a high dose of alcohol by gavage, and this increase was associated with more hepatic endoplasmic reticulum (ER) stress, hepatocyte apoptosis, and lipolysis. Interestingly, in the same binge-drinking model, ALDH2-deficient mice experienced similar liver injury to wild-type animals, despite elevated serum acetaldehyde concentrations (108). Further studies indicated that administering ethanol, but not acetaldehyde, intraperitoneally reproduced the acute liver injury observed with alcohol binge drinking. Additionally, deleting ADH1 led to increased FAEE concentrations after alcohol gavage, while deleting the gene for Ces1d, an FAEE synthetase, reduced the alcohol-induced rise in FAEE concentrations. These findings strongly suggest that alcohol and FAEEs, rather than acetaldehyde, drive acute liver injury (108).
