Glucocorticoid deficiency causes transcriptional and post-transcriptional reprogramming of glutamine metabolism.
Glucocorticoid deficiency causes transcriptional and post-transcriptional reprogramming of glutamine metabolism.
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DOI：
10.1016/j.ebiom.2018.09.024
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发表时间：
2018-10
期刊：
影响因子：
11.1
通讯作者：
Krone N
中科院分区：
文献类型：
--
作者：
Weger M;Weger BD;Görling B;Poschet G;Yildiz M;Hell R;Luy B;Akcay T;Güran T;Dickmeis T;Müller F;Krone N
糖皮质激素生物合成不足导致肾上腺功能不全是危及生命的，并与显著的合并症有关。糖皮质激素缺乏引起的共病的病理生理学基础的受影响途径仍然知之甚少，需要进一步研究。为了探索与糖皮质激素缺乏相关的病理生理过程，我们对一个皮质醇缺乏的斑马鱼突变体进行了转录、转录后和代谢分析，该突变体具有被破坏的铁氧还蛋白（fdx 1b）系统。fdx 1b −/−突变体表现出广泛的代谢重编程，特别是谷氨酰胺依赖性途径，如谷胱甘肽代谢，并表现出氧化应激标志物的变化。参与嘌呤从头合成的关键酶的糖皮质激素依赖性转录后调节也受到影响，在这个突变体。此外，fdx 1b −/−突变体表现出原发性肾上腺功能不全的关键特征，并反映了原发性肾上腺功能不全患者中检测到的代谢变化。我们的研究提供了一个详细的地图糖皮质激素缺乏引起的代谢变化的结果，在肾上腺皮质功能不全的动物模型中的铁氧还蛋白系统的破坏。这种对整体糖皮质激素缺乏症的病理生理学理解的改善为患有糖皮质激素缺乏症相关疾病的人类的更有针对性的翻译研究提供了信息。玛丽·居里欧洲内部职业发展研究金，人类生长因子方案BIFTM，德国研究共同体，BBSRC。
Deficient glucocorticoid biosynthesis leading to adrenal insufficiency is life-threatening and is associated with significant co-morbidities. The affected pathways underlying the pathophysiology of co-morbidities due to glucocorticoid deficiency remain poorly understood and require further investigation. To explore the pathophysiological processes related to glucocorticoid deficiency, we have performed global transcriptional, post-transcriptional and metabolic profiling of a cortisol-deficient zebrafish mutant with a disrupted ferredoxin (fdx1b) system. fdx1b−/− mutants show pervasive reprogramming of metabolism, in particular of glutamine-dependent pathways such as glutathione metabolism, and exhibit changes of oxidative stress markers. The glucocorticoid-dependent post-transcriptional regulation of key enzymes involved in de novo purine synthesis was also affected in this mutant. Moreover, fdx1b−/− mutants exhibit crucial features of primary adrenal insufficiency, and mirror metabolic changes detected in primary adrenal insufficiency patients. Our study provides a detailed map of metabolic changes induced by glucocorticoid deficiency as a consequence of a disrupted ferredoxin system in an animal model of adrenal insufficiency. This improved pathophysiological understanding of global glucocorticoid deficiency informs on more targeted translational studies in humans suffering from conditions associated with glucocorticoid deficiency. Marie Curie Intra-European Fellowships for Career Development, HGF-programme BIFTM, Deutsche Forschungsgemeinschaft, BBSRC.
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影响因子：
9.8
作者：
Dickmeis T;Lahiri K;Nica G;Vallone D;Santoriello C;Neumann CJ;Hammerschmidt M;Foulkes NS
通讯作者：
Foulkes NS
影响因子：
14.9
作者：
Chorley BN;Campbell MR;Wang X;Karaca M;Sambandan D;Bangura F;Xue P;Pi J;Kleeberger SR;Bell DA
通讯作者：
Bell DA
影响因子：
21.3
作者：
Cox AG;Hwang KL;Brown KK;Evason K;Beltz S;Tsomides A;O'Connor K;Galli GG;Yimlamai D;Chhangawala S;Yuan M;Lien EC;Wucherpfennig J;Nissim S;Minami A;Cohen DE;Camargo FD;Asara JM;Houvras Y;Stainier DYR;Goessling W
通讯作者：
Goessling W
影响因子：
46.9
作者：
Gaidatzis, Dimos;Burger, Lukas;Stadler, Michael B.
通讯作者：
Stadler, Michael B.
影响因子：
4.8
作者：
Dhawan, Latika;Liu, Bin;Taubman, Mark B.
通讯作者：
Taubman, Mark B.