Frontiers in Endocrinology (Nov 2023)

PPARG dysregulation as a potential molecular target in adrenal Cushing's syndrome

  • Sharmilee Vetrivel,
  • Mariangela Tamburello,
  • Mariangela Tamburello,
  • Andrea Oßwald,
  • Ru Zhang,
  • Ali Khan,
  • Sara Jung,
  • Jessica E. Baker,
  • William E. Rainey,
  • Elisabeth Nowak,
  • Barbara Altieri,
  • Mario Detomas,
  • Deepika Watts,
  • Tracy Ann Williams,
  • Ben Wielockx,
  • Felix Beuschlein,
  • Felix Beuschlein,
  • Martin Reincke,
  • Silviu Sbiera,
  • Anna Riester

DOI
https://doi.org/10.3389/fendo.2023.1265794
Journal volume & issue
Vol. 14

Abstract

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BackgroundWe performed a transcriptomic analysis of adrenal signaling pathways in various forms of endogenous Cushing’s syndrome (CS) to define areas of dysregulated and druggable targets.MethodologyNext-generation sequencing was performed on adrenal samples of patients with primary bilateral macronodular adrenal hyperplasia (PBMAH, n=10) and control adrenal samples (n=8). The validation groups included cortisol-producing adenoma (CPA, n=9) and samples from patients undergoing bilateral adrenalectomy for Cushing’s disease (BADX-CD, n=8). In vivo findings were further characterized using three adrenocortical cell-lines (NCI-H295R, CU-ACC2, MUC1).ResultsPathway mapping based on significant expression patterns identified PPARG (peroxisome proliferator-activated receptor gamma) pathway as the top hit. Quantitative PCR (QPCR) confirmed that PPARG (l2fc<-1.5) and related genes – FABP4 (l2fc<-5.5), PLIN1 (l2fc<-4.1) and ADIPOQ (l2fc<-3.3) – were significantly downregulated (p<0.005) in PBMAH. Significant downregulation of PPARG was also found in BADX-CD (l2fc<-1.9, p<0.0001) and CPA (l2fc<-1.4, p<0.0001). In vitro studies demonstrated that the PPARG activator rosiglitazone resulted in decreased cell viability in MUC1 and NCI-H295R (p<0.0001). There was also a significant reduction in the production of aldosterone, cortisol, and cortisone in NCI-H295R and in Dihydrotestosterone (DHT) in MUC1 (p<0.05), respectively.OutcomeThis therapeutic effect was independent of the actions of ACTH, postulating a promising application of PPARG activation in endogenous hypercortisolism.

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