Targeting glutamine metabolism in hepatic stellate cells alleviates liver fibrosis
Abstract Glutamine metabolism plays an essential role in cell growth, and glutamate dehydrogenase (GDH) is a key enzyme. GDH promotes the metabolism of glutamate and glutamine to generate ATP, which is profoundly increased in multiple human cancers. Through in vitro and in vivo experiments, we verif...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2022-11-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-022-05409-0 |
| _version_ | 1811318032054616064 |
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| author | Xiaochun Yin Jin Peng Lihong Gu Yan Liu Xihan Li Jinhui Wu Bing Xu Yuzheng Zhuge Feng Zhang |
| author_facet | Xiaochun Yin Jin Peng Lihong Gu Yan Liu Xihan Li Jinhui Wu Bing Xu Yuzheng Zhuge Feng Zhang |
| author_sort | Xiaochun Yin |
| collection | DOAJ |
| description | Abstract Glutamine metabolism plays an essential role in cell growth, and glutamate dehydrogenase (GDH) is a key enzyme. GDH promotes the metabolism of glutamate and glutamine to generate ATP, which is profoundly increased in multiple human cancers. Through in vitro and in vivo experiments, we verified that the small-molecule GDH inhibitor EGCG slowed the progression of fibrosis by inhibiting GDH enzyme activity and glutamine metabolism. SIRT4 is a mitochondrial enzyme with NAD that promotes ADP ribosylation and downregulates GDH activity. The role of SIRT4 in liver fibrosis and the related mechanisms are unknown. In this study, we measured the expression of SIRT4 and found that it was downregulated in liver fibrosis. Modest overexpression of SIRT4 protected the liver from fibrosis by inhibiting the transformation of glutamate to 2-ketoglutaric acid (α-KG) in the tricarboxylic acid cycle (TCA), thereby reducing the proliferative activity of hepatic stellate cells (HSCs). Collectively, our study reveals that SIRT4 controls GDH enzyme activity and expression, targeting glutamine metabolism in HSCs and alleviating liver fibrosis. |
| first_indexed | 2024-04-13T12:19:50Z |
| format | Article |
| id | doaj.art-d0b49f6a88534e73a2302632f73c613d |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-04-13T12:19:50Z |
| publishDate | 2022-11-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-d0b49f6a88534e73a2302632f73c613d2022-12-22T02:47:16ZengNature Publishing GroupCell Death and Disease2041-48892022-11-0113111910.1038/s41419-022-05409-0Targeting glutamine metabolism in hepatic stellate cells alleviates liver fibrosisXiaochun Yin0Jin Peng1Lihong Gu2Yan Liu3Xihan Li4Jinhui Wu5Bing Xu6Yuzheng Zhuge7Feng Zhang8Department of Gastroenterology, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical SchoolHepatobiliary and Pancreatic Center & Liver Transplantation Center, the Affiliated Drum Tower Hospital, Medical School of Nanjing UniversityDepartment of Gastroenterology, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical SchoolDepartment of Gastroenterology, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical SchoolDepartment of Gastroenterology, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical SchoolState Key Laboratory of Pharmaceutical Biotechnology, Chemistry and Biomedicine Innovation Center, Medical School, Nanjing UniversityDepartment of Gastroenterology, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical SchoolDepartment of Gastroenterology, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical SchoolDepartment of Gastroenterology, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical SchoolAbstract Glutamine metabolism plays an essential role in cell growth, and glutamate dehydrogenase (GDH) is a key enzyme. GDH promotes the metabolism of glutamate and glutamine to generate ATP, which is profoundly increased in multiple human cancers. Through in vitro and in vivo experiments, we verified that the small-molecule GDH inhibitor EGCG slowed the progression of fibrosis by inhibiting GDH enzyme activity and glutamine metabolism. SIRT4 is a mitochondrial enzyme with NAD that promotes ADP ribosylation and downregulates GDH activity. The role of SIRT4 in liver fibrosis and the related mechanisms are unknown. In this study, we measured the expression of SIRT4 and found that it was downregulated in liver fibrosis. Modest overexpression of SIRT4 protected the liver from fibrosis by inhibiting the transformation of glutamate to 2-ketoglutaric acid (α-KG) in the tricarboxylic acid cycle (TCA), thereby reducing the proliferative activity of hepatic stellate cells (HSCs). Collectively, our study reveals that SIRT4 controls GDH enzyme activity and expression, targeting glutamine metabolism in HSCs and alleviating liver fibrosis.https://doi.org/10.1038/s41419-022-05409-0 |
| spellingShingle | Xiaochun Yin Jin Peng Lihong Gu Yan Liu Xihan Li Jinhui Wu Bing Xu Yuzheng Zhuge Feng Zhang Targeting glutamine metabolism in hepatic stellate cells alleviates liver fibrosis Cell Death and Disease |
| title | Targeting glutamine metabolism in hepatic stellate cells alleviates liver fibrosis |
| title_full | Targeting glutamine metabolism in hepatic stellate cells alleviates liver fibrosis |
| title_fullStr | Targeting glutamine metabolism in hepatic stellate cells alleviates liver fibrosis |
| title_full_unstemmed | Targeting glutamine metabolism in hepatic stellate cells alleviates liver fibrosis |
| title_short | Targeting glutamine metabolism in hepatic stellate cells alleviates liver fibrosis |
| title_sort | targeting glutamine metabolism in hepatic stellate cells alleviates liver fibrosis |
| url | https://doi.org/10.1038/s41419-022-05409-0 |
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