ArticleRedox biology2022
Inhibition of GCN2 alleviates hepatic steatosis and oxidative stress in obese mice: Involvement of NRF2 regulation.
Article in Redox biology, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 48 citations in OpenAlex.
- Leucyl tRNA synthetase ameliorates cholestatic liver injury by inhibiting integrated stress response in mice.Scientific reports · 2026Article
- Extracellular vesicles derived by hypoxic preconditioned EPCs attenuated atherosclerosis by suppressing ferroptosis via regulating arginine metabolism.Redox biology · 2026Article
- Mechanisms of mTORC1 and GCN2 amino acid sensing pathways in tumorigenesis and metastatic progression (Review).International journal of molecular medicine · 2026Review
- Traditional Chinese medicine in the treatment of diabetic kidney disease: the mechanisms of signaling pathways regulations.Frontiers in endocrinology · 2026Review
- Overcoming immunotherapy resistance in breast cancer: a novel strategy by targeting the integrated stress response.Frontiers in cell and developmental biology · 2026Review
- From inflammation to remodelling: A novel BASP1Journal of advanced research · 2025Article
- Macrophage ferroptosis potentiates GCN2 deficiency induced pulmonary venous arterialization.Nature communications · 2025Article
- Interpreting ribosome dynamics during mRNA translation.The Journal of biological chemistry · 2025Review
- The clinical antiprotozoal drug halofuginone promotes weight loss by elevating GDF15 and FGF21.Science advances · 2025Article
- Human brain proteome-wide association study provides insights into the genetic components of protein abundance in obesity.International journal of obesity (2005) · 2024Article
- PSMD11 loss-of-function variants correlate with a neurobehavioral phenotype, obesity, and increased interferon response.American journal of human genetics · 2024Article
- Homotherapy for heteropathy: therapeutic effect of Butein in NLRP3-driven diseases.Cell communication and signaling : CCS · 2024Article
- Emerging Role of GCN1 in Disease and Homeostasis.International journal of molecular sciences · 2024Review
- Research progress on the correlation between cataract occurrence and nutrition.Frontiers in nutrition · 2024Review
- Tissue adaptation to metabolic stress: insights from SUMOylation.Frontiers in endocrinology · 2024Review
- Erhong Jiangzhi Decoction Inhibits Lipid Accumulation and Alleviates Nonalcoholic Fatty Liver Disease with Nrf2 Restoration Under Obesity.Journal of inflammation research · 2024Article
- Hepatic DDAH1 mitigates hepatic steatosis and insulin resistance in obese mice: Involvement of reduced S100A11 expression.Acta pharmaceutica Sinica. B · 2023Article
- Surviving and Adapting to Stress: Translational Control and the Integrated Stress Response.Antioxidants & redox signaling · 2023Review
- The signaling pathways of traditional Chinese medicine in treating diabetic retinopathy.Frontiers in pharmacology · 2023Review
- Genetic and Pharmacological Inhibition of GCN2 Ameliorates Hyperglycemia and Insulin Resistance in Type 2 Diabetic Mice.Antioxidants (Basel, Switzerland) · 2022Article
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
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.
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