New Insights into Alcohol-Induced Liver Damage: Formation of 'Pseudosynapses' and Inflammation Mechanisms

Excessive alcohol intake leads to serious liver conditions, including alcoholic liver disease (ALD), which can progress to steatohepatitis and ultimately result in liver failure. Recent research from KAIST and Seoul National University Boramae Medical Center has uncovered a novel molecular mechanism underlying alcohol-related liver damage. The study reveals that damaged hepatocytes, or liver cells, tend to form specialized structures called 'pseudosynapses' with Kupffer cells—the liver's resident immune cells. These pseudosynapses resemble synapses found in the brain and facilitate direct communication between these cell types.

This interaction begins when chronic alcohol consumption increases the expression of VGLUT3, a transporter responsible for glutamate, leading to its accumulation in liver cells. Binge drinking then triggers rapid calcium fluctuations within hepatocytes, causing them to release glutamate. This glutamate binds to mGluR5 receptors on Kupffer cells, inducing the production of reactive oxygen species (ROS). The resulting pathway causes cell death and stimulates inflammation, contributing to liver injury.

A groundbreaking aspect of this research is the discovery that injured hepatocytes and Kupffer cells can physically attach through the pseudosynapse, allowing direct signal transmission—a phenomenon previously thought exclusive to neural tissues. This structure enables the damaged liver cells to send distress signals that activate immune responses and potentially promote liver regeneration.

The study also demonstrated that inhibiting key components of this pathway, such as VGLUT3, mGluR5, or NOX2 (an enzyme involved in ROS production), can reduce alcohol-induced liver damage in animal models. These findings were corroborated by analyzing blood and liver tissue samples from patients with ALD, confirming the relevance of the mechanism in humans.

Professor Jeong highlighted that these insights open new avenues for diagnosing and treating alcohol-associated liver conditions early and effectively. The research team, including co-authors Dr. Keungmo Yang and Kyurae Kim, believes targeting these molecular pathways can lead to innovative therapies for ALD, potentially halting its progression and aiding liver regeneration.