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

Research output: Contribution to journalArticle

Authors

  • Benjamin D. Weger
  • Benjamin Görling
  • Gernot Poschet
  • Melek Yildiz
  • Rüdiger Hell
  • Burkhard Luy
  • Teoman Akcay
  • Tülay Güran
  • Thomas Dickmeis

External organisations

  • Karlsruhe Institute of Technology
  • Heidelberg University
  • Kanuni Sultan Süleyman Education and Research Hospital, Küçükçekmece, Istanbul, Turkey.
  • Istinye University
  • Marmara University
  • Institute of Toxicology and Genetics, Karlsruhe Institute of Technology

Abstract

Background: 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.

Methods: 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.

Findings: 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.

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

Details

Original languageEnglish
Pages (from-to)376-389
Number of pages14
JournalEBioMedicine
Volume36
Early online date26 Sep 2018
Publication statusPublished - Oct 2018

Keywords

  • zebrafish, ferrodoxin, adrenal insufficiency, oxidative stress, purine metabolism