E47 as a novel glucocorticoid-dependent gene mediating lipid metabolism in patients with endogenous glucocorticoid excess

Wei Zhang, Hanna Nowotny, Marily Theodoropoulou, Julia Simon, Charlotte M. Hemmer, Martin Bidlingmaier, Matthias K. Auer, Martin Reincke, Henriette Uhlenhaut, Nicole Reisch

Research output: Contribution to journalArticlepeer-review

Abstract

Purpose: E47 has been identified as a modulating transcription factor of glucocorticoid receptor target genes, its loss protecting mice from metabolic adverse effects of glucocorticoids. We aimed to analyze the role of E47 in patients with endogenous glucocorticoid excess [Cushing’s syndrome (CS)] and its association with disorders of lipid and glucose metabolism. Methods: This is a prospective cohort study including 120 female patients with CS (ACTH-dependent = 79; ACTH-independent = 41) and 26 healthy female controls. Morning whole blood samples after an overnight fast were used to determine E47 mRNA expression levels in patients with overt CS before and 6–12 months after curative surgery. Expression levels were correlated with the clinical phenotype of the patients. Control subjects underwent ACTH stimulation tests and dexamethasone suppression tests to analyze short-term regulation of E47. Results: E47 gene expression showed significant differences in patient cohorts with overt CS vs. patients in remission (p = 0.0474) and in direct intraindividual comparisons pre- vs. post-surgery (p = 0.0353). ACTH stimulation of controls resulted in a significant decrease of E47 mRNA expression 30 min after i.v. injection compared to baseline measurements. Administration of 1 mg of dexamethasone overnight in controls did not change E47 mRNA expression. E47 gene expression showed a positive correlation with total serum cholesterol (p = 0.0036), low-density lipoprotein cholesterol (p = 0.0157), and waist–arm ratio (p = 0.0138) in patients with CS in remission. Conclusion: E47 is a GC-dependent gene that is upregulated in GC excess potentially aiming at reducing metabolic glucocorticoid side effects such as dyslipidemia.

Original languageEnglish
Article number1249863
JournalFrontiers in Endocrinology
Volume14
DOIs
StatePublished - 2023

Keywords

  • ACTH
  • comorbidity
  • cortisol
  • Cushing’s disease
  • Cushing’s syndrome
  • dyslipidemia
  • transcription factor 3

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