Inhibition of GCN2 alleviates hepatic steatosis and oxidative stress in obese mice: Involvement of NRF2 regulation.
Inhibition of GCN2 alleviates hepatic steatosis and oxidative stress in obese mice: Involvement of NRF2 regulation.
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DOI：
10.1016/j.redox.2021.102224
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发表时间：
2022-03
期刊：
影响因子：
11.4
通讯作者：
Lu Z
中科院分区：
文献类型：
--
作者：
Yuan J;Yu Z;Gao J;Luo K;Shen X;Cui B;Lu Z
非酒精性脂肪性肝病(NAFLD)的发生与活性氧(ROS)的产生增加有关。在不同营养条件下，一般控制不可降压2(GCN2)在调节肝脏氧化还原状态中的相互矛盾的作用引起了对GCN2调节ROS动态平衡的潜在机制的研究。在本研究中，发现GCN2与NRF2相互作用，并以Keap1依赖的方式降低NRF2的表达。通过增加GSK-3β活性，去亮氨酸或常山酮激活GCN2可降低肝细胞中NRF2的表达。作为对氧化应激的响应，GCN2抑制了NRF2的转录活性。通过尾静脉注射AAV8-shGcn2载体敲除肝脏GCN2以NRF2依赖的方式减轻瘦素缺乏(ob/ob)小鼠的肝脏脂肪变性和氧化应激。GCN2iB抑制GCN2还改善了ob/ob小鼠和高脂饮食喂养小鼠的肝脏脂肪变性和氧化应激，这与脂质和氨基酸代谢途径的显著变化有关。非靶向代谢组学分析显示，GCN2iB降低了脂肪肝中脂肪酸和鞘磷脂的水平，但增加了脂肪肝中的脂肪氨基酸和磷脂酰胆碱的水平。总之，我们的结果提供了第一个直接证据，证明GCN2是NRF2的一个新的调节因子，以及特定的GCN2抑制剂可能是治疗NAFLD的潜在药物。GCN2与NRF2相互作用，并以Keap1依赖的方式降低NRF2的表达。氨基酸饥饿激活GCN2可通过提高GSK-3β活性来降低NRF2的表达。GCN2基因敲除以NRF2依赖的方式减轻肝脏脂肪变性和氧化应激。抑制GCN2可减轻肥胖小鼠的肝脏脂肪变性和氧化应激。
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. GCN2 interacts with NRF2 and decreases NRF2 expression in a KEAP1-dependent manner. Activation of GCN2 by amino acid starvation decreases NRF2 expression by increasing GSK-3β activity. GCN2 knockdown attenuates hepatic steatosis and oxidative stress in an NRF2-dependent manner. Inhibition of GCN2 alleviates hepatic steatosis and oxidative stress in obese mice.
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影响因子：
14.8
作者：
Keller, Tracy L.;Zocco, Davide;Sundrud, Mark S.;Hendrick, Margaret;Edenius, Maja;Yum, Jinah;Kim, Yeon-Jin;Lee, Hak-Kyo;Cortese, Joseph F.;Wirth, Dyann F.;Dignam, John David;Rao, Anjana;Yeo, Chang-Yeol;Mazitschek, Ralph;Whitman, Malcolm
通讯作者：
Whitman, Malcolm
影响因子：
10.5
作者：
Itoh, K;Wakabayashi, N;Yamamoto, M
通讯作者：
Yamamoto, M
影响因子：
16
作者：
Harding, HP;Novoa, I;Ron, D
通讯作者：
Ron, D
DOI：
10.1152/ajpendo.90617.2008
发表时间：
2008-12-01
影响因子：
5.1
作者：
Andrikopoulos, Sofianos;Blair, Amy R.;Proietto, Joseph
通讯作者：
Proietto, Joseph
影响因子：
21.3
作者：
Komatsu, Masaaki;Kurokawa, Hirofumi;Yamamoto, Masayuki
通讯作者：
Yamamoto, Masayuki