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...
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Nature Portfolio
2025-07-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-60820-3 |
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| author | Keungmo Yang Kyurae Kim Tom Ryu Young-Ri Shim Hee-Hoon Kim Sung Eun Choi Min Jeong Kim Katherine Po Sin Chung Eunmi Lee Kwang Woo Lee Jehwi Jeon Pilhan Kim Young Seo Kim Taeyun Ku Haengdueng Jeong Ki Taek Nam Gyumin Lim Dong Wook Choi Seok-Hwan Kim Hyuk Soo Eun Won Kim Won-Il Jeong |
| author_facet | Keungmo Yang Kyurae Kim Tom Ryu Young-Ri Shim Hee-Hoon Kim Sung Eun Choi Min Jeong Kim Katherine Po Sin Chung Eunmi Lee Kwang Woo Lee Jehwi Jeon Pilhan Kim Young Seo Kim Taeyun Ku Haengdueng Jeong Ki Taek Nam Gyumin Lim Dong Wook Choi Seok-Hwan Kim Hyuk Soo Eun Won Kim Won-Il Jeong |
| author_sort | Keungmo Yang |
| collection | DOAJ |
| description | 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 interference of mGluR5 or NOX2 in KCs alleviates alcohol-related steatohepatitis (ASH). Analysis of patient samples confirmed some of the findings from mice, showing that plasma glutamate concentration and VGLUT3 levels correlate with ASH development. Conclusively, our findings highlight glutamate storage and release in mediating ASH, particularly through the pseudosynapse between hepatocytes and KCs. |
| format | Article |
| id | doaj-art-fa56000db9044c70858ecda1d98c82a9 |
| institution | DOAJ |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-fa56000db9044c70858ecda1d98c82a92025-08-20T03:03:37ZengNature PortfolioNature Communications2041-17232025-07-0116111710.1038/s41467-025-60820-3Binge drinking triggers VGLUT3-mediated glutamate secretion and subsequent hepatic inflammation by activating mGluR5/NOX2 in Kupffer cellsKeungmo Yang0Kyurae Kim1Tom Ryu2Young-Ri Shim3Hee-Hoon Kim4Sung Eun Choi5Min Jeong Kim6Katherine Po Sin Chung7Eunmi Lee8Kwang Woo Lee9Jehwi Jeon10Pilhan Kim11Young Seo Kim12Taeyun Ku13Haengdueng Jeong14Ki Taek Nam15Gyumin Lim16Dong Wook Choi17Seok-Hwan Kim18Hyuk Soo Eun19Won Kim20Won-Il Jeong21Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST)Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST)Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST)Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST)Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST)Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST)Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST)Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST)Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST)Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST)Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST)Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST)Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST)Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST)Department of Biomedical Sciences, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of MedicineDepartment of Biomedical Sciences, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of MedicineDepartment of Biotechnology, College of Life Sciences and Biotechnology, Korea UniversityDepartment of Biotechnology, College of Life Sciences and Biotechnology, Korea UniversityDepartment of Surgery, Chungnam National University, College of MedicineDepartment of Internal Medicine, Chungnam National University School of MedicineDivision of Gastroenterology and Hepatology, Department of Internal Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul National University College of MedicineGraduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST)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 interference of mGluR5 or NOX2 in KCs alleviates alcohol-related steatohepatitis (ASH). Analysis of patient samples confirmed some of the findings from mice, showing that plasma glutamate concentration and VGLUT3 levels correlate with ASH development. Conclusively, our findings highlight glutamate storage and release in mediating ASH, particularly through the pseudosynapse between hepatocytes and KCs.https://doi.org/10.1038/s41467-025-60820-3 |
| spellingShingle | Keungmo Yang Kyurae Kim Tom Ryu Young-Ri Shim Hee-Hoon Kim Sung Eun Choi Min Jeong Kim Katherine Po Sin Chung Eunmi Lee Kwang Woo Lee Jehwi Jeon Pilhan Kim Young Seo Kim Taeyun Ku Haengdueng Jeong Ki Taek Nam Gyumin Lim Dong Wook Choi Seok-Hwan Kim Hyuk Soo Eun Won Kim Won-Il Jeong Binge drinking triggers VGLUT3-mediated glutamate secretion and subsequent hepatic inflammation by activating mGluR5/NOX2 in Kupffer cells Nature Communications |
| title | Binge drinking triggers VGLUT3-mediated glutamate secretion and subsequent hepatic inflammation by activating mGluR5/NOX2 in Kupffer cells |
| title_full | Binge drinking triggers VGLUT3-mediated glutamate secretion and subsequent hepatic inflammation by activating mGluR5/NOX2 in Kupffer cells |
| title_fullStr | Binge drinking triggers VGLUT3-mediated glutamate secretion and subsequent hepatic inflammation by activating mGluR5/NOX2 in Kupffer cells |
| title_full_unstemmed | Binge drinking triggers VGLUT3-mediated glutamate secretion and subsequent hepatic inflammation by activating mGluR5/NOX2 in Kupffer cells |
| title_short | Binge drinking triggers VGLUT3-mediated glutamate secretion and subsequent hepatic inflammation by activating mGluR5/NOX2 in Kupffer cells |
| title_sort | binge drinking triggers vglut3 mediated glutamate secretion and subsequent hepatic inflammation by activating mglur5 nox2 in kupffer cells |
| url | https://doi.org/10.1038/s41467-025-60820-3 |
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