Chronic alcohol consumption reprograms hepatic metabolism through organelle-specific acetylation in mice.

Post-translational acetylation of proteins by acetyl-CoA is a crucial regulator of proteostasis and substrate metabolism. Ethanol metabolism in the liver induces protein accumulation, acetylation and metabolic disruption. While acetylation impacts enzyme activity and stability, its role in ethanol-related protein accumulation and metabolic dysfunction remains unclear. Using stable isotope-based proteomics, acetylomics, and metabolic profiling in a mouse model of chronic ethanol-induced liver injury, we demonstrate that ethanol induces hepatic steatosis, inflammation, oxidative stress, and proteinopathy linked to altered protein turnover. Ethanol increased the cytosolic protein turnover related to oxidative stress and detoxification, while reducing turnover of mitochondrial metabolic enzymes. It also elevated the acetylation of mitochondrial enzymes and nuclear histones with minimal cytosolic changes, impairing mitochondrial protein degradation. These changes were associated with altered levels of acyl-CoAs and acyl-carnitines, amino acids, and tricarboxylic acid (TCA) cycle intermediates, reflecting impaired fatty acid oxidation, nitrogen disposal and TCA cycle activities. These results suggest that ethanol-induced acetylation contributes to liver injury and that targeting acetylation may offer treatment for alcohol-induced liver diseases.