GLYAT deficiency protects against acetaminophen-induced liver injury by increasing glycine availability for glutathione synthesis.

Drug-induced liver injury is the most common cause of acute liver failure in Western countries, but the choice of effective antidotes is restricted in most conditions. Glycine-N-acyltransferase (GLYAT) catalyzes the conjugation of glycine to acyl-CoA, serving as a crucial phase II metabolic enzyme for hepatic detoxification. However, few studies have clarified the role of GLYAT in drug-induced liver injury. Our study showed that hepatic glycine level and Glyat expression were reduced upon APAP exposure, but restored within 12 h, similar to the change of hepatic glutathione (GSH). This dynamic expression pattern may be regulated by liver-enriched transcription factors such as HNF4A identified through promoter analysis. Glyat knockout in female mice reduced circulating alanine transaminase (ALT), aspartate transaminase (AST), hepatic reactive oxygen species (ROS) and phosphorylated c-Jun N-terminal kinase (JNK) / extracellular regulated protein kinases (ERK) levels. Conversely, overexpression of Glyat by injection of adeno-associated virus 8 (AAV8) in female mice displayed exacerbated phenotypes, including elevated serum transaminases, increased oxidative stress, enhanced mitogen-activated protein kinase (MAPK) signaling and aggravated hepatocellular necrosis. However, neither Glyat deletion nor overexpression in male mice had effects on APAP toxicity. These protective effects were associated with increased hepatic glycine and GSH levels, as well as attenuated oxidative stress and inflammatory responses. In addition, glycine supplementation had similar hepatoprotective effects to Glyat deficiency in female mice. Taken together, these findings identify GLYAT as a potential therapeutic target and suggest that glycine supplementation may serve as an adjuvant therapy for APAP-induced liver damage, particularly in females.