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

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

  • Sharmilee Vetrivel - , Hospital of the Ludwig-Maximilians-University (LMU) Munich (Author)
  • Mariangela Tamburello - , University Hospital Olomouc (Author)
  • Andrea Oßwald - , Hospital of the Ludwig-Maximilians-University (LMU) Munich (Author)
  • Ru Zhang - , Hospital of the Ludwig-Maximilians-University (LMU) Munich (Author)
  • Ali Khan - , University Hospital Olomouc (Author)
  • Sara Jung - , Hospital of the Ludwig-Maximilians-University (LMU) Munich (Author)
  • Jessica E Baker - , University of Michigan Medical School (Author)
  • William E Rainey - , University of Michigan Medical School (Author)
  • Elisabeth Nowak - , Hospital of the Ludwig-Maximilians-University (LMU) Munich (Author)
  • Barbara Altieri - , University Hospital Olomouc (Author)
  • Mario Detomas - , University Hospital Olomouc (Author)
  • Deepika Watts - , Institute of Clinical Chemistry and Laboratory Medicine (Author)
  • Tracy Ann Williams - , Hospital of the Ludwig-Maximilians-University (LMU) Munich (Author)
  • Ben Wielockx - , Institute of Clinical Chemistry and Laboratory Medicine (Author)
  • Felix Beuschlein - , Hospital of the Ludwig-Maximilians-University (LMU) Munich (Author)
  • Martin Reincke - , Hospital of the Ludwig-Maximilians-University (LMU) Munich (Author)
  • Silviu Sbiera - , University Hospital Olomouc (Author)
  • Anna Riester - , Hospital of the Ludwig-Maximilians-University (LMU) Munich (Author)

Abstract

BACKGROUND: We 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.

METHODOLOGY: Next-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).

RESULTS: Pathway 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.

OUTCOME: This therapeutic effect was independent of the actions of ACTH, postulating a promising application of PPARG activation in endogenous hypercortisolism.

Details

Original languageEnglish
Article number1265794
Pages (from-to)1265794
JournalFrontiers in endocrinology
Volume14
Publication statusPublished - 30 Nov 2023
Peer-reviewedYes

External IDs

PubMedCentral PMC10720662
Scopus 85179690811

Keywords

Keywords

  • Adrenalectomy/methods, Cushing Syndrome/genetics, Humans, Hydrocortisone/metabolism, Hyperplasia, PPAR gamma/genetics