Binge drinking triggers VGLUT3-mediated glutamate secretion and subsequent hepatic inflammation by activating mGluR5/NOX2 in Kupffer cells.

ABSTRACT: Glutamate, a crucial player in hepatic amino acid metabolism, has been relatively unexplored in immune cell activation. We show in a study with male mice that hepatic glutamate accumulates in vesicles of perivenous hepatocytes through vesicular glutamate transporter 3 (VGLUT3), regulated by the aryl hydrocarbon receptor upon chronic alcohol intake. Additional binge drinking triggers the exocytosis of glutamate by altering the intracellular Ca²⁺ level, stimulating metabotropic glutamate receptor 5 (mGluR5) and subsequent NADPH oxidase 2 (NOX2)-mediated ROS production in Kupffer cells (KCs). This interaction between hepatocytes and KCs is facilitated by pseudosynapse formation, arising from alcohol-induced ballooning of perivenous hepatocytes. Genetic or pharmacological interferen

SUBMITTER: Yang K 

PROVIDER: S-EPMC12216207 | biostudies-literature | 2025 Jul

REPOSITORIES: biostudies-literature