PUBLICATION

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

Authors

Weger, M., Weger, B.D., Görling, B., Poschet, G., Yildiz, M., Hell, R., Luy, B., Akcay, T., Güran, T., Dickmeis, T., Müller, F., Krone, N.

ID

ZDB-PUB-180930-1

Date

2018

Source

EBioMedicine 36: 376-389 (Journal)

Registered Authors

Dickmeis, Thomas, Müller, Ferenc, Weger, Benjamin, Weger, Meltem

Keywords

Adrenal insufficiency, Ferredoxin, Oxidative stress, Purine metabolism, Zebrafish

Datasets

GEO:GSE107547

MeSH Terms

Animals
Adrenal Insufficiency/metabolism*
Metabolomics
Zebrafish/genetics
Zebrafish/metabolism
Glutamine/metabolism*
Glucocorticoids/biosynthesis
Humans
Animals, Genetically Modified
Metabolic Networks and Pathways*

(all 10)

PubMed

30266295 Full text @ EBioMedicine

Abstract

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.

Genes / Markers

Figures

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Expression

Gene	Fish	Conditions	Stage	Anatomy	Assay	Figure
atic	fdx1b^{uob205/uob205}	control	Day 5	whole organism	RTPCR	Fig. 5
atic	fdx1b^{uob205/uob205}	chemical treatment by environment: dexamethasone	Day 5	whole organism	RTPCR	Fig. 5
atic	s705Tg	control	Day 5	whole organism	RTPCR	Fig. S4
atic	WT	control	Day 5	whole organism	RTPCR	Fig. S4
atic	WT	control	Day 5	whole organism	RTPCR	Fig. 5
atic	WT	chemical treatment by environment: dexamethasone	Day 5	whole organism	RTPCR	Fig. 5
cyp17a2	fdx1b^{uob205/uob205}	standard conditions	Day 5	interrenal gland	ISH	Fig. 6
cyp17a2	WT	standard conditions	Day 5	interrenal gland	ISH	Fig. 6
duox	fdx1b^{uob205/uob205}	control	Day 5	whole organism	RTPCR	Fig. S3
duox	fdx1b^{uob205/uob205}	chemical treatment by environment: dexamethasone	Day 5	whole organism	RTPCR	Fig. S3

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Phenotype

Fish	Conditions	Stage	Phenotype	Figure
WT	chemical treatment by environment: dexamethasone	Day 5	whole organism gls2a expression increased amount, abnormal	Fig. 3
WT	chemical treatment by environment: dexamethasone	Day 5	whole organism gls2b expression increased amount, abnormal	Fig. 3
fdx1b^{uob205/uob205}	control	Day 5	glutathione metabolic process process quality, abnormal	Fig. 4
fdx1b^{uob205/uob205}	control	Day 5	whole organism atic expression increased amount, abnormal	Fig. 5
fdx1b^{uob205/uob205}	control	Day 5	whole organism duox expression increased amount, abnormal	Fig. S3
fdx1b^{uob205/uob205}	control	Day 5	whole organism fth1a expression increased amount, abnormal	Fig. S3
fdx1b^{uob205/uob205}	control	Day 5	whole organism gls2a expression decreased amount, abnormal	Fig. 3
fdx1b^{uob205/uob205}	control	Day 5	whole organism gls2b expression decreased amount, abnormal	Fig. 3
fdx1b^{uob205/uob205}	control	Day 5	whole organism paics expression increased amount, abnormal	Fig. 5
fdx1b^{uob205/uob205}	control	Day 5	whole organism ADP increased amount, abnormal	Fig. 5

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Mutations / Transgenics

Allele	Construct	Type	Affected Genomic Region
s705Tg	Tg(-2.8fabp10a:yap1_S87A,cryaa:Venus)	Transgenic Insertion
t25181		Point Mutation	rx3
t25327		Point Mutation	rx3
uob205		Small Deletion	fdx1b

1 - 4 of 4

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Human Disease / Model

Sequence Targeting Reagents

Fish

Fish
fdx1b^{uob205/uob205}
rx3^{t25181/t25181}
rx3^{t25327/t25327}
s705Tg
WT

Antibodies

Orthology

Engineered Foreign Genes

Marker	Marker Type	Name
Venus	EFG	Venus

Mapping

Weger et al., 2018 ZDB-PUB-180930-1 PMID:30266295

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

Weger et al., 2018

ZDB-PUB-180930-1
PMID:30266295