AdipoRon mitigates liver fibrosis by suppressing serine/glycine biosynthesis through ATF4-dependent glutaminolysis
AdipoRon has been validated for its ability to reverse liver fibrosis, yet the underlying mechanisms remain to be thoroughly investigated. Collagen, predominantly synthesized and secreted in hepatic stellate cells (HSCs), relies on glycine as a crucial constituent. Activating transcription factor 4...
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Elsevier
2025-01-01
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| Series: | Ecotoxicology and Environmental Safety |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0147651324015872 |
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| author | Xiangting Zhang Yuan Zeng Huiya Ying Yiwen Hong Jun Xu Rong Lin Yuhao Chen Xiao Wu Weimin Cai Ziqiang Xia Qian Zhao Yixiao Wang Ruoru Zhou Dandan Zhu Fujun Yu |
| author_facet | Xiangting Zhang Yuan Zeng Huiya Ying Yiwen Hong Jun Xu Rong Lin Yuhao Chen Xiao Wu Weimin Cai Ziqiang Xia Qian Zhao Yixiao Wang Ruoru Zhou Dandan Zhu Fujun Yu |
| author_sort | Xiangting Zhang |
| collection | DOAJ |
| description | AdipoRon has been validated for its ability to reverse liver fibrosis, yet the underlying mechanisms remain to be thoroughly investigated. Collagen, predominantly synthesized and secreted in hepatic stellate cells (HSCs), relies on glycine as a crucial constituent. Activating transcription factor 4 (ATF4) serves as a pivotal transcriptional regulator in amino acid metabolism. Therefore, our objective is to explore the impact of AdipoRon on ATF4-mediated endoplasmic reticulum stress and amino acid metabolism in HSCs. We induced liver fibrosis in mice through intraperitoneal injection of CCl4 and administered AdipoRon (50 mg/kg) via gavage. In vitro studies were predominantly conducted using LX-2 cells. Our findings demonstrated that AdipoRon effectively suppressed ATF4-mediated endoplasmic reticulum stress in HSCs and assumed a crucial role in hindering serine/glycine biosynthesis. Interestingly, this inhibitory effect of AdipoRon on serine/glycine biosynthesis is regulated by PSAT1-mediated glutaminolysis, resulting in a subsequent decrease in collagen synthesis within HSCs. This study provides potential mechanistic insights into the treatment of liver fibrosis with AdipoRon. |
| format | Article |
| id | doaj-art-06ea96215a8145f28e214e7fc2c9be6b |
| institution | Kabale University |
| issn | 0147-6513 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Ecotoxicology and Environmental Safety |
| spelling | doaj-art-06ea96215a8145f28e214e7fc2c9be6b2025-01-23T05:25:49ZengElsevierEcotoxicology and Environmental Safety0147-65132025-01-01289117511AdipoRon mitigates liver fibrosis by suppressing serine/glycine biosynthesis through ATF4-dependent glutaminolysisXiangting Zhang0Yuan Zeng1Huiya Ying2Yiwen Hong3Jun Xu4Rong Lin5Yuhao Chen6Xiao Wu7Weimin Cai8Ziqiang Xia9Qian Zhao10Yixiao Wang11Ruoru Zhou12Dandan Zhu13Fujun Yu14Department of Gastroenterology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, ChinaDepartment of Gastroenterology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, ChinaDepartment of Gastroenterology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, ChinaWenzhou Medical University, Wenzhou, Zhejiang, ChinaDepartment of Gastroenterology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, ChinaDepartment of Gastroenterology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, ChinaDepartment of Gastroenterology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, ChinaDepartment of Gastroenterology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, ChinaDepartment of Gastroenterology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, ChinaDepartment of Gastroenterology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, ChinaDepartment of Gastroenterology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, ChinaDepartment of Gastroenterology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, ChinaDepartment of Gastroenterology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, ChinaDepartment of Gastroenterology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, ChinaDepartment of Gastroenterology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China; Corresponding author.AdipoRon has been validated for its ability to reverse liver fibrosis, yet the underlying mechanisms remain to be thoroughly investigated. Collagen, predominantly synthesized and secreted in hepatic stellate cells (HSCs), relies on glycine as a crucial constituent. Activating transcription factor 4 (ATF4) serves as a pivotal transcriptional regulator in amino acid metabolism. Therefore, our objective is to explore the impact of AdipoRon on ATF4-mediated endoplasmic reticulum stress and amino acid metabolism in HSCs. We induced liver fibrosis in mice through intraperitoneal injection of CCl4 and administered AdipoRon (50 mg/kg) via gavage. In vitro studies were predominantly conducted using LX-2 cells. Our findings demonstrated that AdipoRon effectively suppressed ATF4-mediated endoplasmic reticulum stress in HSCs and assumed a crucial role in hindering serine/glycine biosynthesis. Interestingly, this inhibitory effect of AdipoRon on serine/glycine biosynthesis is regulated by PSAT1-mediated glutaminolysis, resulting in a subsequent decrease in collagen synthesis within HSCs. This study provides potential mechanistic insights into the treatment of liver fibrosis with AdipoRon.http://www.sciencedirect.com/science/article/pii/S0147651324015872Hepatic stellate cellsendoplasmic reticulum stressglutaminolysiscollagenliver fibrosis |
| spellingShingle | Xiangting Zhang Yuan Zeng Huiya Ying Yiwen Hong Jun Xu Rong Lin Yuhao Chen Xiao Wu Weimin Cai Ziqiang Xia Qian Zhao Yixiao Wang Ruoru Zhou Dandan Zhu Fujun Yu AdipoRon mitigates liver fibrosis by suppressing serine/glycine biosynthesis through ATF4-dependent glutaminolysis Ecotoxicology and Environmental Safety Hepatic stellate cells endoplasmic reticulum stress glutaminolysis collagen liver fibrosis |
| title | AdipoRon mitigates liver fibrosis by suppressing serine/glycine biosynthesis through ATF4-dependent glutaminolysis |
| title_full | AdipoRon mitigates liver fibrosis by suppressing serine/glycine biosynthesis through ATF4-dependent glutaminolysis |
| title_fullStr | AdipoRon mitigates liver fibrosis by suppressing serine/glycine biosynthesis through ATF4-dependent glutaminolysis |
| title_full_unstemmed | AdipoRon mitigates liver fibrosis by suppressing serine/glycine biosynthesis through ATF4-dependent glutaminolysis |
| title_short | AdipoRon mitigates liver fibrosis by suppressing serine/glycine biosynthesis through ATF4-dependent glutaminolysis |
| title_sort | adiporon mitigates liver fibrosis by suppressing serine glycine biosynthesis through atf4 dependent glutaminolysis |
| topic | Hepatic stellate cells endoplasmic reticulum stress glutaminolysis collagen liver fibrosis |
| url | http://www.sciencedirect.com/science/article/pii/S0147651324015872 |
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