GCN2 is required to increase fibroblast growth factor 21 and maintain hepatic triglyceride homeostasis during asparaginase treatment.
GCN2 is required to increase fibroblast growth factor 21 and maintain hepatic triglyceride homeostasis during asparaginase treatment.
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DOI：
10.1152/ajpendo.00361.2014
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发表时间：
2015-02
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影响因子：
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通讯作者：
G. Wilson;Brittany A. Lennox;Pengxiang She;Emily T Mirek;Rana J. T. Al Baghdadi;Michael E Fusakio;J. Dixon;Gregory C. Henderson;R. Wek;T. Anthony
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文献类型：
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作者：
G. Wilson;Brittany A. Lennox;Pengxiang She;Emily T Mirek;Rana J. T. Al Baghdadi;Michael E Fusakio;J. Dixon;Gregory C. Henderson;R. Wek;T. Anthony
抗白血病药物天冬酰胺酶通过激活真核起始因子2（eIF 2）激酶一般控制非去阻遏蛋白2（GCN 2）触发肝脏中的氨基酸反应（AAR）。为了探索AAR诱导对于减轻肝脂质积累和预防持续天冬酰胺酶治疗期间肝功能障碍是必要的机制，每天一次向野生型和Gcn 2缺失小鼠注射天冬酰胺酶或磷酸盐缓冲盐水，持续长达14天。天冬酰胺酶诱导多种AAR基因的mRNA表达，并显著增加代谢激素成纤维细胞生长因子21（FGF 21）的循环浓度，而与食物摄入无关。Gcn 2的缺失阻止了肝脏和白色脂肪组织中FGF 21的mRNA表达和循环水平，并阻断了多种调节脂质合成和代谢的基因的mRNA表达，包括Fas、Ppara、Pparg、Acadm和Scd 1。此外，甘油三酯输出率和载脂蛋白B-100的蛋白质表达显着降低Gcn 2基因敲除小鼠的肝脏与天冬酰胺酶治疗，提供了一个机制的基础上，肝脂质含量的增加。Gcn 2缺失肝脏中AAR调节的抗氧化防御功能的丧失通过Gpx 1基因表达的减少以及脂质过氧化的增加来表示。天冬酰胺酶处理的Gcn 2基因敲除小鼠血液中抗凝血酶III肝脏表达和活性的显著降低表明肝功能障碍。这些结果表明，肝脏适应长时间天冬酰胺酶治疗的能力受到GCN 2指导的FGF 21调节和氧化防御的影响，当失去时，对应于对脂质代谢和止血的适应不良影响。
The antileukemic agent asparaginase triggers the amino acid response (AAR) in the liver by activating the eukaryotic initiation factor 2 (eIF2) kinase general control nonderepressible 2 (GCN2). To explore the mechanism by which AAR induction is necessary to mitigate hepatic lipid accumulation and prevent liver dysfunction during continued asparaginase treatment, wild-type and Gcn2 null mice were injected once daily with asparaginase or phosphate buffered saline for up to 14 days. Asparaginase induced mRNA expression of multiple AAR genes and greatly increased circulating concentrations of the metabolic hormone fibroblast growth factor 21 (FGF21) independent of food intake. Loss of Gcn2 precluded mRNA expression and circulating levels of FGF21 and blocked mRNA expression of multiple genes regulating lipid synthesis and metabolism including Fas, Ppara, Pparg, Acadm, and Scd1 in both liver and white adipose tissue. Furthermore, rates of triglyceride export and protein expression of apolipoproteinB-100 were significantly reduced in the livers of Gcn2 null mice treated with asparaginase, providing a mechanistic basis for the increase in hepatic lipid content. Loss of AAR-regulated antioxidant defenses in Gcn2 null livers was signified by reduced Gpx1 gene expression alongside increased lipid peroxidation. Substantial reductions in antithrombin III hepatic expression and activity in the blood of asparaginase-treated Gcn2 null mice indicated liver dysfunction. These results suggest that the ability of the liver to adapt to prolonged asparaginase treatment is influenced by GCN2-directed regulation of FGF21 and oxidative defenses, which, when lost, corresponds with maladaptive effects on lipid metabolism and hemostasis.