Dysregulated hepatic alcohol metabolism: a key factor involved in the pathogenesis of alcohol-associated liver disease

Alcohol use disorder is a major risk factor for alcohol-associated liver disease (ALD), characterized by reduced hepatic alcohol dehydrogenase (ADH) activity, increased body burden of alcohol, and its nonoxidative metabolism to fatty acid ethyl esters (FAEEs). However, the mechanism(s) underlying ALD remain unclear. This study investigated the metabolic basis and mechanism(s) of ALD in chronic ethanol (EtOH)-fed hepatic ADH1-deficient (ADH^-) deer mice administered with a single dose of binge EtOH with/without FAEEs. Hepatic ADH^- and ADH normal (ADH⁺) deer mice fed chronic EtOH daily for 3 mo, followed by a single dose of binge EtOH (3 g/kg·body wt) with/without FAEEs (100 mg/kg·body wt), 1 wk before euthanasia. Blood alcohol and acetaldehyde and liver injury markers in the plasma, hepatic FAEEs, lipids, and inflammatory markers were analyzed. Hepatic histology, ultrastructure, protein/mRNA expression of genes involved in alcohol metabolism and lipogenesis, cyclic adenosine monophosphate (cAMP), phosphodiesterase (PDE) activity, and AMP-activated protein kinase (AMPKα) signaling were assessed. Blood alcohol, hepatic lipids and FAEEs, inflammation, oxidative stress, and the expression of lipogenic proteins/genes were significantly increased in various chronic EtOH-fed groups of ADH^- versus ADH⁺ deer mice. In addition, hepatic cAMP levels were reduced, whereas PDE activity and plasma transaminases were elevated. Binge EtOH with/without FAEEs did not significantly exacerbate the liver injury in chronic EtOH-fed ADH^- as well as ADH⁺ deer mice. Overall, an increased body burden of EtOH and endogenously formed FAEEs due to hepatic ADH deficiency, along with dysregulated cAMP and AMPKα signaling, could be the determining factors for EtOH-induced liver injury leading to ALD.