Glutamatergic metabolic synapses between hepatocytes and Kupffer cells in liver disease

Professor Won-Il Jeong’s group at KAIST has elucidated the molecular mechanisms underlying alcohol-associated steatohepatitis (ASH), highlighting the formation of glutamate-driven crosstalk between hepatocytes and Kupffer cells—resembling a “pseudosynapse.” These findings define key molecular signaling pathways involved in ASH pathogenesis.

Following chronic alcohol consumption, the synthesis (OAT, ALDH4A1) and transport (EAAT2) of glutamate are upregulated, accompanied by the accumulation of vesicles containing glutamate (VGLUT3) in perivenous hepatocytes. In contrast, binge drinking triggers a rapid release of hepatic glutamate, driven by fluctuations in intracellular calcium levels. This glutamate secretion exacerbates alcohol-induced liver inflammation through activation of the glutamate receptor mGluR5 on liver-resident macrophages (Kupffer cells). The resulting production of reactive oxygen species (ROS) helps clear damaged hepatocytes and thus promote tissue regeneration. Notably, genetic and pharmacological inhibition of glutamate transport between hepatocytes and Kupffer cells significantly attenuates ASH progression.

During ASH development, damaged hepatocytes act as primary drivers of inflammation by secreting glutamate as a signaling molecule. The glutamate-mediated interaction between ballooned, alcohol-injured hepatocytes and Kupffer cells is facilitated by their physical proximity, mimicking neuronal signal transduction. Similar to neuronal communication, glutamate secretion is regulated by intracellular calcium dynamics and SNARE complex formation. The newly proposed concept of a “pseudosynapse or metabolic synapse” in peripheral organs may have broader implications for other diseases and their underlying mechanisms. Accordingly, the research team emphasized the role of metabolic synapse formation in peripheral tissues and the active contribution of hepatocytes as key initiators of alcohol-induced liver injury.

Professor Jeong remarked, “This discovery may pave the way for novel diagnostic and therapeutic targets for early-stage alcohol-associated liver diseases.”

The study was published on 1 July 2025 (Binge drinking triggers VGLUT3-mediated glutamate secretion and subsequent hepatic inflammation by activating mGluR5/NOX2 in Kupffer cells, Nature Communications, 16, 5546 (2025). This work was supported by a National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT): RS-2021-NR059919 (W.I.J.), 2021R1A2C2005820 (W.K), RS-2021-NR056442 (W.K.), RS-2022-NR067269 (W.I.J), RS-2023-00223831 (W.I.J.).