A new molecular mechanism has been identified in South Korea, revealing for the first time in the world that alcohol consumption generates reactive oxygen species (ROS), which induce hepatocyte death and inflammatory responses. The study also discovered a new neurological pathway in which hepatocytes form 'pseudosynapses'?structures similar to synapses in the nervous system?to exchange signals and trigger inflammation.
On July 17, KAIST announced that a research team led by Professor Wonil Jung from the Graduate School of Medical Science and Engineering, in collaboration with Professor Won Kim's team at Seoul National University Boramae Medical Center, has elucidated the molecular mechanisms underlying alcohol-induced liver injury and inflammation (alcoholic steatohepatitis). This breakthrough provides important clues for the diagnosis and treatment of alcoholic liver disease.
Dr. Kyungmo Yang, Professor Wonil Jung, and PhD candidate Kyurae Kim from the Graduate School of Medical Science and Engineering at KAIST. Provided by KAIST
The joint research team confirmed that chronic alcohol consumption increases the expression of the vesicular glutamate transporter (VGLUT3), leading to glutamate accumulation in hepatocytes. Subsequently, binge drinking causes a rapid change in intracellular calcium concentrations, which in turn induces glutamate secretion.
They also discovered that the secreted glutamate stimulates the glutamate receptor (mGluR5) on Kupffer cells, which are resident macrophages in the liver. This stimulation triggers the production of reactive oxygen species, forming a pathological pathway that leads to hepatocyte death and inflammatory responses.
Glutamate, a type of amino acid, is involved in intercellular signaling, protein synthesis, and energy metabolism across various tissues, including the brain and liver. However, excessive glutamate can cause overexcitation of neurons, resulting in cellular damage or death.
This study is significant in that it is the first to demonstrate that, during alcohol consumption, hepatocytes and Kupffer cells in the liver temporarily form pseudosynapses?structures similar to synapses observed only in the nervous system?to exchange signals.
Pseudosynapses, also known as metabolic synapses, are formed when alcohol-induced ballooning of hepatocytes brings them into close physical contact with Kupffer cells. The joint research team explained that damaged hepatocytes do not simply die; instead, they send signals to adjacent Kupffer cells to induce an immune response.
This discovery introduces a new paradigm, showing that signal transmission through close structural contact between cells is possible even in peripheral organs. Furthermore, the study confirms that, beyond simple hepatocyte injury, alcohol-damaged hepatocytes can actively stimulate macrophages to induce regeneration through cell death, revealing an 'autonomous recovery function.'
In animal models, the joint research team demonstrated that genetic or pharmacological inhibition of glutamate transporters, glutamate receptors, and reactive oxygen species-generating enzymes (NOX2) can partially suppress alcohol-mediated liver injury.
They also analyzed blood and liver tissue samples from patients with alcoholic liver disease, suggesting that this mechanism can be clinically applicable.
Professor Wonil Jung stated, "The findings of our joint research team could serve as new molecular targets for diagnosis or treatment in the early stages of alcoholic steatohepatitis in the future."
This research was supported by the Global Leader Research Program, the Mid-Career Researcher Program, and the Bio-Medical Technology Development Program of the National Research Foundation of Korea, funded by the Ministry of Science and ICT.
This study was jointly conducted by Dr. Kyungmo Yang (currently at Yeouido St. Mary's Hospital) and PhD candidate Kyurae Kim from the KAIST Graduate School of Medical Science and Engineering as co-first authors, together with Professor Won Kim's team at Seoul National University Boramae Medical Center. The results (paper) were published in the international journal 'Nature Communications' on July 1.
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