DC Field | Value | Language |
---|---|---|
dc.contributor.advisor | 정원일 | - |
dc.contributor.author | Yang, Keungmo | - |
dc.contributor.author | 양경모 | - |
dc.date.accessioned | 2024-07-26T19:31:37Z | - |
dc.date.available | 2024-07-26T19:31:37Z | - |
dc.date.issued | 2023 | - |
dc.identifier.uri | http://library.kaist.ac.kr/search/detail/view.do?bibCtrlNo=1052048&flag=dissertation | en_US |
dc.identifier.uri | http://hdl.handle.net/10203/321152 | - |
dc.description | 학위논문(박사) - 한국과학기술원 : 의과학대학원, 2023.2,[v, 72 p. :] | - |
dc.description.abstract | Recently, the crosstalk between hepatocytes (HEPs) and hepatic stellate cells via glutamate signaling was reported to play a pivotal role in alcohol-associated steatosis. However, the precise role of hepatic glutamate in the pathogenesis of alcoholic-associated steatohepatitis (ASH) is still largely unexplored. Here, I investigated the accumulative process of alcohol-induced glutamate vesicles (GVs) in HEPs. Furthermore, I elucidated that glutamate excreted from HEPs induces inflammatory liver injury by the activation of metabotropic glutamate receptor 5 (mGluR5) in Kupffer cells (KCs). After chronic alcohol consumption in mice, hepatic expressions of ALDH4A1 and vesicular glutamate transporter 3 (VGLUT3) were upregulated for the glutamate synthesis and storage, respectively, through nuclear factor erythroid-2-related factor 2 (NRF2)-aryl hydrocarbon receptor (AHR) pathway. Simultaneously, alcohol-induced ballooning of HEPs creates pseudo-synaptic clefts between HEPs and KCs to facilitate the interaction of glutamate and mGluR5. After 2-week ethanol feeding, binge drinking rapidly altered the intracellular calcium levels to trigger the exocytosis of VGLUT3$^+$ GVs, and the released glutamate stimulated reactive oxygen species (ROS) production in KCs through mGluR5 activation. Moreover, I found that mGluR5 activation induced NOX2-mediated ROS generation through protein kinase C (PKC) in KCs. Accordingly, the pharmacologic inhibitions of hepatic GV formation or PKC in KCs remarkably reduced alcohol-induced liver injury. KC-specific mGluR5 or NADPH oxidase 2 deficient mice significantly attenuated inflammatory liver injury. In human samples, I consistently demonstrated that glutamate released from vesicles has a positive correlation with the inflammatory markers in ASH patients without liver cirrhosis. In this study, I firstly demonstrated that the alcohol-induced ‘pseudo-synaptic cleft’ between HEPs and KCs mediates the development of alcohol-associated liver disease (ALD) via vesicular glutamate signaling, and provides the novel molecular targets for the ALD treatment. | - |
dc.language | eng | - |
dc.publisher | 한국과학기술원 | - |
dc.subject | 알코올성 간질환▼a간세포 풍선화▼a글루타메이트 과립▼a글루타메이트 수용체▼a쿠퍼세포▼a활성 산소 | - |
dc.subject | Alcohol-associated liver disease▼aHepatocyte ballooning▼aVesicular glutamate transporter 3▼aGlutamate vesicle▼aMetabotropic glutamate receptor 5▼aKupffer cell▼aReactive oxygen species | - |
dc.title | Mechanism study of the inflammatory injury by glutamate vesicles in hepatocytes and glutamate receptor activation in Kupffer cells in alcohol-associated liver disease | - |
dc.title.alternative | 알코올성 간질환에서 글루타메이트 과립의 형성과 쿠퍼세포의 글루타메이트 수용체 활성화를 통한 염증성 손상 기전 규명 | - |
dc.type | Thesis(Ph.D) | - |
dc.identifier.CNRN | 325007 | - |
dc.description.department | 한국과학기술원 :의과학대학원, | - |
dc.contributor.alternativeauthor | Jeong, Won-Il | - |
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