GLP-1 receptor agonism results in reduction in hepatic ethanol metabolism

Glucagon-like peptide 1 receptor (GLP-1R) agonists are used along with ethanol consumption, but their interactions are not understood. Our aim was to determine the effects of GLP-1R agonism on the liver in mouse models of high ethanol consumption. We identified that GLP-1R agonism reduced ethanol consumption, mitigated ethanol-induced upregulation of several liver metabolizing enzymes, including Cyp2e1 and also reduced Cyp2e1 independent of ethanol intake. As expected from a reduction in Cyp2e1, GLP-1R agonism resulted in increased blood ethanol levels. This occurred after a single dose of ethanol when given by gavage, and by the intraperitoneal route. This suggests that GLP-1R agonism can reduce ethanol-mediated hepatotoxicity despite continued ethanol consumption and elevate blood alcohol levels 24 mice were divided into four groups—1) Control (CT), 2) Alcohol-fed (ALC), 3) Alcohol + GLP-1R agonist (ALC + GLP), 4) Control + GLP-1R agonist (CT + GLP). The semaglutide dosage regimen was escalated from 1 to 30 nmol/kg over 16 days. On day 16, mice in the alcohol groups received alcohol gavage, and control groups received dextrin.