Inhibition of GCN2 alleviates hepatic steatosis and oxidative stress in obese mice: Involvement of NRF2 regulation
The development of nonalcoholic fatty liver disease (NAFLD) is associated with increased reactive oxygen species (ROS) production. Previous observations on the contradictory roles of general control nonderepressible 2 (GCN2) in regulating the hepatic redox state under different nutritional condition...
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| Format: | Article |
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Elsevier
2022-02-01
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| Series: | Redox Biology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213231721003840 |
| _version_ | 1818978432745209856 |
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| author | Juntao Yuan Zhuoran Yu Junling Gao Kai Luo Xiyue Shen Bingqing Cui Zhongbing Lu |
| author_facet | Juntao Yuan Zhuoran Yu Junling Gao Kai Luo Xiyue Shen Bingqing Cui Zhongbing Lu |
| author_sort | Juntao Yuan |
| collection | DOAJ |
| description | The development of nonalcoholic fatty liver disease (NAFLD) is associated with increased reactive oxygen species (ROS) production. Previous observations on the contradictory roles of general control nonderepressible 2 (GCN2) in regulating the hepatic redox state under different nutritional conditions prompted an investigation of the underlying mechanism by which GCN2 regulates ROS homeostasis. In the present study, GCN2 was found to interact with NRF2 and decrease NRF2 expression in a KEAP1-dependent manner. Activation of GCN2 by halofuginone treatment or leucine deprivation decreased NRF2 expression in hepatocytes by increasing GSK-3β activity. In response to oxidative stress, GCN2 repressed NRF2 transcriptional activity. Knockdown of hepatic GCN2 by tail vein injection of an AAV8-shGcn2 vector attenuated hepatic steatosis and oxidative stress in leptin-deficient (ob/ob) mice in an NRF2-dependent manner. Inhibition of GCN2 by GCN2iB also ameliorated hepatic steatosis and oxidative stress in both ob/ob mice and high fat diet-fed mice, which was associated with significant changes in lipid and amino acid metabolic pathways. Untargeted metabolomics analysis revealed that GCN2iB decreased fatty acid and sphingomyelin levels but increased aliphatic amino acid and phosphatidylcholine levels in fatty livers. Collectively, our results provided the first direct evidence that GCN2 is a novel regulator of NRF2 and that specific GCN2 inhibitors might be potential drugs for NAFLD therapy. |
| first_indexed | 2024-12-20T16:43:33Z |
| format | Article |
| id | doaj.art-2df94e71262a4e73b259cbc44b5a34ae |
| institution | Directory Open Access Journal |
| issn | 2213-2317 |
| language | English |
| last_indexed | 2024-12-20T16:43:33Z |
| publishDate | 2022-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Redox Biology |
| spelling | doaj.art-2df94e71262a4e73b259cbc44b5a34ae2022-12-21T19:32:58ZengElsevierRedox Biology2213-23172022-02-0149102224Inhibition of GCN2 alleviates hepatic steatosis and oxidative stress in obese mice: Involvement of NRF2 regulationJuntao Yuan0Zhuoran Yu1Junling Gao2Kai Luo3Xiyue Shen4Bingqing Cui5Zhongbing Lu6College of Life Science, University of Chinese Academy of Sciences, Beijing, 100049, ChinaCollege of Life Science, University of Chinese Academy of Sciences, Beijing, 100049, ChinaCollege of Life Science, University of Chinese Academy of Sciences, Beijing, 100049, ChinaCollege of Life Science, University of Chinese Academy of Sciences, Beijing, 100049, ChinaCollege of Life Science, University of Chinese Academy of Sciences, Beijing, 100049, ChinaCollege of Life Science, University of Chinese Academy of Sciences, Beijing, 100049, ChinaCorresponding author. College of Life Science, University of Chinese Academy of Sciences, 19A Yuquanlu, Beijing, 100049, China.; College of Life Science, University of Chinese Academy of Sciences, Beijing, 100049, ChinaThe development of nonalcoholic fatty liver disease (NAFLD) is associated with increased reactive oxygen species (ROS) production. Previous observations on the contradictory roles of general control nonderepressible 2 (GCN2) in regulating the hepatic redox state under different nutritional conditions prompted an investigation of the underlying mechanism by which GCN2 regulates ROS homeostasis. In the present study, GCN2 was found to interact with NRF2 and decrease NRF2 expression in a KEAP1-dependent manner. Activation of GCN2 by halofuginone treatment or leucine deprivation decreased NRF2 expression in hepatocytes by increasing GSK-3β activity. In response to oxidative stress, GCN2 repressed NRF2 transcriptional activity. Knockdown of hepatic GCN2 by tail vein injection of an AAV8-shGcn2 vector attenuated hepatic steatosis and oxidative stress in leptin-deficient (ob/ob) mice in an NRF2-dependent manner. Inhibition of GCN2 by GCN2iB also ameliorated hepatic steatosis and oxidative stress in both ob/ob mice and high fat diet-fed mice, which was associated with significant changes in lipid and amino acid metabolic pathways. Untargeted metabolomics analysis revealed that GCN2iB decreased fatty acid and sphingomyelin levels but increased aliphatic amino acid and phosphatidylcholine levels in fatty livers. Collectively, our results provided the first direct evidence that GCN2 is a novel regulator of NRF2 and that specific GCN2 inhibitors might be potential drugs for NAFLD therapy.http://www.sciencedirect.com/science/article/pii/S2213231721003840GCN2NRF2KEAP1Hepatic steatosisOxidative stress |
| spellingShingle | Juntao Yuan Zhuoran Yu Junling Gao Kai Luo Xiyue Shen Bingqing Cui Zhongbing Lu Inhibition of GCN2 alleviates hepatic steatosis and oxidative stress in obese mice: Involvement of NRF2 regulation Redox Biology GCN2 NRF2 KEAP1 Hepatic steatosis Oxidative stress |
| title | Inhibition of GCN2 alleviates hepatic steatosis and oxidative stress in obese mice: Involvement of NRF2 regulation |
| title_full | Inhibition of GCN2 alleviates hepatic steatosis and oxidative stress in obese mice: Involvement of NRF2 regulation |
| title_fullStr | Inhibition of GCN2 alleviates hepatic steatosis and oxidative stress in obese mice: Involvement of NRF2 regulation |
| title_full_unstemmed | Inhibition of GCN2 alleviates hepatic steatosis and oxidative stress in obese mice: Involvement of NRF2 regulation |
| title_short | Inhibition of GCN2 alleviates hepatic steatosis and oxidative stress in obese mice: Involvement of NRF2 regulation |
| title_sort | inhibition of gcn2 alleviates hepatic steatosis and oxidative stress in obese mice involvement of nrf2 regulation |
| topic | GCN2 NRF2 KEAP1 Hepatic steatosis Oxidative stress |
| url | http://www.sciencedirect.com/science/article/pii/S2213231721003840 |
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