Glucocorticoid deficiency causes transcriptional and post-transcriptional reprogramming of glutamine metabolism.

Meltem Weger,Tülay Güran,Melek Yildiz,Nils Krone,Gernot Poschet,Burkhard Luy,Benjamin D Weger,Thomas Dickmeis,Teoman Akcay,Benjamin Görling,Ferenc Müller,Rüdiger Hell

doi:10.1016/j.ebiom.2018.09.024

Abstract

BackgroundDeficient 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.MethodsTo 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.Findingsfdx1b−/− 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.InterpretationOur 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.FundMarie Curie Intra-European Fellowships for Career Development, HGF-programme BIFTM, Deutsche Forschungsgemeinschaft, BBSRC.

Highlights

Glucocorticoids (GCs) are crucial regulators of important physiological functions including metabolism [45]
A further more specific analysis of metabolic pathways based on KEGG annotation [74] identified an expected compensatory up-regulation of genes involved in steroid hormone synthesis in response to the disrupted steroidogenesis (Fig. 1B)
Given the importance of glutamine for de novo purine synthesis (Fig. 5A), we explored if the observed changes in glutamine metabolism with down-regulation of gls2a and gls2b in fdx1b−/− mutants are linked to the altered mRNA stability of paics and atic

Summary

Introduction

Glucocorticoids (GCs) are crucial regulators of important physiological functions including metabolism [45]. The pathophysiological mechanisms of altered metabolism due to glucocorticoid deficiency are not precisely understood and warrant further investigation Such an endeavor is, almost impossible in humans. We employed a zebrafish mutant with impaired mitochondrial glucocorticoid biosynthesis to explore global changes in metabolites and gene expression at both the transcriptional and post-transcriptional level. Interpretation: 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. Fund: Marie Curie Intra-European Fellowships for Career Development, HGF-programme BIFTM, Deutsche Forschungsgemeinschaft, BBSRC

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