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Nat. Commun., Published: 01 July 2025;16, 5546 | https://doi.org/10.1038/s41467-025-60820-3
Binge drinking triggers VGLUT3-mediated glutamate secretion and subsequent hepatic inflammation by activating mGluR5/NOX2 in Kupffer cells
Keungmo Yang1,2,10, Kyurae Kim1,10, Tom Ryu1, Young-Ri Shim1, Hee-Hoon Kim1, Sung Eun Choi1, Min Jeong Kim1, Katherine Po Sin Chung1, Eunmi Lee1, Kwang Woo Lee1, Jehwi Jeon1,3, Pilhan Kim1, Young Seo Kim1, Taeyun Ku1, Haengdueng Jeong4, Ki Taek Nam4, Gyumin Lim5, Dong Wook Choi5, Seok-Hwan Kim6, Hyuk Soo Eun7, Won Kim8 & Won-Il Jeong1,9
1Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea.
2Division of Gastroenterology and Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
3Institute of Vision Research, Department of Ophthalmology, Severance Eye Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
4Department of Biomedical Sciences, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea.
5Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea.
6Department of Surgery, Chungnam National University, College of Medicine, Daejeon, Republic of Korea.
7Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon, Republic of Korea.
8Division of Gastroenterology and Hepatology, Department of Internal Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul National University College of Medicine, Seoul, Republic of Korea.
9Center for the Hepatic Glutamate and Its Function, KAIST, Daejeon, Republic of Korea.
10These authors contributed equally: Keungmo Yang, Kyurae Kim.
Corresponding authors
Correspondence to Won Kim or Won-Il Jeong.
1Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea.
2Division of Gastroenterology and Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
3Institute of Vision Research, Department of Ophthalmology, Severance Eye Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
4Department of Biomedical Sciences, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea.
5Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea.
6Department of Surgery, Chungnam National University, College of Medicine, Daejeon, Republic of Korea.
7Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon, Republic of Korea.
8Division of Gastroenterology and Hepatology, Department of Internal Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul National University College of Medicine, Seoul, Republic of Korea.
9Center for the Hepatic Glutamate and Its Function, KAIST, Daejeon, Republic of Korea.
10These authors contributed equally: Keungmo Yang, Kyurae Kim.
Corresponding authors
Correspondence to Won Kim or Won-Il Jeong.
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.
논문정보
- Research article
- 2025년 07월 (BRIC 등록일 2025-07-02)
- 국내 연구진
- 의약학 > 분자세포의학
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