Metabolic Profiling of Glucocorticoid Deficiency: A “Fishing” Expedition

Alexander Pott; Steffen Just

摘要

Adrenal insufficiency (AI) is a life-threatening metabolic disorder in humans leading to severe symptoms such as fatigue, abdominal pain, infection, reduced heart rate as well as decreased blood pressure. On a pathophysiological level AI is defined as impaired synthesis of various adrenal hormones including the glucocorticoid hormone cortisol [1]. Current therapeutic strategies are routinely based on cortisol replacement by oral drug therapy. However, this therapy is far downstream of the disease triggering mechanism, since reduced adrenal hormone synthesis can be caused by the impairment of various signaling pathways in different organs. Glucocorticoid hormone replacement reduces morbidity and mortality in AI patients, nevertheless, this therapeutic approach is non-curative and associated with severe adverse side effects [2,3]. To extend our knowledge of AI and to optimize current therapeutic strategies, more mechanistic insights of genetic and molecular pathways and networks involved in this severe metabolic disorder are pivotal.In the last two decades the zebrafish has been established as an excellent tool to decipher the genetic as well as molecular underpinnings of various human diseases, including metabolic or cardiovascular disorders [[4], [5], [6]]. Interestingly, several studies comparing development and function of the endocrine systems demonstrated a high degree of similarity between humans and zebrafish. Thus, important metabolic key molecules in the endocrine system especially the stress axis were dissected in detail in zebrafish [7,8]. As in humans, glucocorticoid hormones play an important role in the response to intrinsic or extrinsic stress triggers in zebrafish and are released by the interrenal gland, the homolog of the adrenal gland in humans. Mitochondrial glucocorticoid synthesis in zebrafish depends on proper Fdx1b function, which is a paralogue of human FDX1 (ferredoxin 1). Remarkably, in 2016 Griffin and co-workers established a stable fdx1b-deficient zebrafish mutant line, demonstrating limited glucocorticoid synthesis leading to a dysfunctional stress axis and primary adrenal insufficiency [9].Recently published in EBioMedicine [10], using their fdx1b-deficient zebrafish mutant line, Weger and coworkers now analyzed the impact of impaired mitochondrial glucocorticoid biosynthesis on metabolism and gene expression and compared their findings to a zebrafish model of secondary adrenal insufficiency (rx3 strong) but also to metabolic data derived from patients suffering from primary adrenal insufficiency.They found that fdx1b-deficient zebrafish show increased glutamine levels as a consequence of reduced glucocorticoid-dependent transcription of liver and intestine specific glutaminases (gls2a and gsl2b) and thereby impaired glutaminolysis. Moreover, biosynthesis of the important antioxidant and cell signaling molecule glutathione was significantly reduced in Fdx1b mutant zebrafish leading to increased levels of oxidative stress markers as well as increased up-regulation of genes involved in DNA repair. Also, the authors found that post-transcriptional regulation of enzymes that are crucial for de novo purine biosynthesis (paics and atic) strongly depends on glucocorticoids. Finally, the authors compared metabolic profiles derived from fdx1b-deficient zebrafish (primary adrenal insufficiency), from rx3 strong mutant zebrafish (secondary adrenal insufficiency) and from patients with primary hypocorticolism. Interestingly, the authors identified overlapping but also distinct changes of metabolic and transcriptional profiles with a higher degree of similarity between fdx1b-deficient zebrafish and patients suffering from primary adrenal insufficiency compared to rx3 strong mutant zebrafish. These findings further strengthen the role of fdx1b mutant zebrafish as a valid animal disease model for human primary adrenal insufficiency.Diagnosis and therapy of adrenal insufficiency in patients are still far from being optimal. The interpretation of cortisol levels as readout for adrenal function, particularly in diverse clinical situations, is often challenging. In this context, the development of novel specific biomarkers e.g. by detailed metabolic and transcriptional profiling would significantly improve the efficient diagnosis of adrenal insufficiency. Furthermore, current steroid replacement in AI patients is unable to fully restore the physiological feedback mechanisms of the hypothalamic-pituitary-adrenal axis. Also, circadian as well as pulsatile hormone secretion is not reconstituted by this therapeutic strategy. A detailed understanding of the pathogenesis of adrenal insufficiency, particularly the metabolic peculiarities of primary and secondary adrenal insufficiency might help to develop therapeutic strategies that specifically target these metabolic differences thereby providing a tailored therapy for patients with primary and secondary adrenal insufficiency.In conclusion, the study

机译：肾上腺皮质功能不全（AI）是威胁人类生命的新陈代谢疾病，导致严重的症状，如疲劳，腹痛，感染，心率降低以及血压降低。在病理生理学水平上，AI被定义为包括糖皮质激素激素皮质醇在内的各种肾上腺激素的合成受损[1]。当前的治疗策略通常基于通过口服药物治疗的皮质醇替代。然而，由于肾上腺激素合成的减少可能是由不同器官中各种信号通路的损伤引起的，因此该疗法在疾病触发机制的下游。糖皮质激素的替代降低了AI患者的发病率和死亡率，但是，这种治疗方法是非治愈性的，并伴有严重的不良副作用[2,3]。为了扩展我们对AI的了解并优化当前的治疗策略，对这种严重代谢紊乱所涉及的遗传和分子途径及网络的更多机理性见解至关重要。在过去的二十年中，斑马鱼已被确立为解密遗传学的极佳工具以及各种人类疾病的分子基础，包括新陈代谢或心血管疾病[[4]，[5]，[6]]。有趣的是，一些比较内分泌系统发育和功能的研究表明，人与斑马鱼之间具有高度相似性。因此，在斑马鱼中详细解剖了内分泌系统中重要的代谢关键分子，尤其是应激轴[7,8]。与人类一样，糖皮质激素在斑马鱼对内在或外在压力触发的反应中起着重要作用，并由肾上腺（人类的肾上腺同源物）释放。斑马鱼的线粒体糖皮质激素合成取决于适当的Fdx1b功能，这是人FDX1（铁氧还蛋白1）的旁系同源物。值得注意的是，2016年，格里芬（Griffin）和同事建立了稳定的fdx1b缺陷型斑马鱼突变体系，证明糖皮质激素合成受限，导致压力轴功能异常和原发性肾上腺皮质功能不全[9]。斑马鱼突变体系，Weger和同事现在分析了线粒体糖皮质激素生物合成受损对代谢和基因表达的影响，并将他们的发现与继发性肾上腺皮质功能不全（rx3强）的斑马鱼模型进行了比较，还与源自原发性肾上腺功能不全患者的代谢数据进行了比较他们发现，缺乏fdx1b的斑马鱼显示出谷氨酰胺水平升高，这是由于肝脏和肠道特异性谷氨酰胺酶（gls2a和gsl2b）的糖皮质激素依赖性转录降低，从而影响了谷氨酰胺分解。此外，重要的抗氧化剂和细胞信号分子谷胱甘肽的生物合成在Fdx1b突变斑马鱼中显着减少，导致氧化应激标志物水平增加以及参与DNA修复的基因上调增加。此外，作者发现，对于从头嘌呤生物合成至关重要的酶（paics和atic）的转录后调节在很大程度上取决于糖皮质激素。最后，作者比较了来自fdx1b缺陷型斑马鱼（原发性肾上腺皮质功能不全），rx3强突变型斑马鱼（继发性肾上腺功能不全）和原发性皮质激素缺乏症患者的代谢特征。有趣的是，与rx3强突变斑马鱼相比，fdx1b缺陷型斑马鱼与患有原发性肾上腺功能不全的患者之间的代谢和转录谱变化具有相似性，但作者发现了重叠但又明显的变化。这些发现进一步增强了fdx1b突变斑马鱼作为人类原发性肾上腺功能不全的有效动物疾病模型的作用。患者肾上腺功能不全的诊断和治疗仍远未达到最佳状态。将皮质醇水平解释为肾上腺功能的读数，尤其是在各种临床情况下，通常具有挑战性。在这种情况下，新型特异性生物标记的开发例如通过详细的代谢和转录谱分析，可以显着改善肾上腺皮质功能不全的有效诊断。此外，目前AI患者中的类固醇替代不能完全恢复下丘脑-垂体-肾上腺轴的生理反馈机制。同样，这种治疗策略也不能重建昼夜节律以及搏动激素的分泌。详细了解肾上腺功能不全的发病机理，尤其是原发性和继发性肾上腺功能不全的代谢特点可能有助于制定针对这些代谢差异的治疗策略，从而为患有原发性和继发性肾上腺功能不全的患者提供量身定制的治疗方法。研究

Metabolic Profiling of Glucocorticoid Deficiency: A “Fishing” Expedition

摘要

著录项

相似文献

相关主题

期刊订阅