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

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

JOURNAL=Frontiers in Endocrinology

VOLUME=14

YEAR=2023

URL=https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2023.1265794

DOI=10.3389/fendo.2023.1265794

ISSN=1664-2392

ABSTRACT=<sec><title>Background</title><p>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.</p></sec><sec><title>Methodology</title><p>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). <italic>In vivo</italic> findings were further characterized using three adrenocortical cell-lines (NCI-H295R, CU-ACC2, MUC1).</p></sec><sec><title>Results</title><p>Pathway mapping based on significant expression patterns identified PPARG (peroxisome proliferator-activated receptor gamma) pathway as the top hit. Quantitative PCR (QPCR) confirmed that <italic>PPARG</italic> (l2fc&lt;-1.5) and related genes – <italic>FABP4</italic> (l2fc&lt;-5.5), <italic>PLIN1</italic> (l2fc&lt;-4.1) and <italic>ADIPOQ</italic> (l2fc&lt;-3.3) – were significantly downregulated (p&lt;0.005) in PBMAH. Significant downregulation of <italic>PPARG</italic> was also found in BADX-CD (l2fc&lt;-1.9, p&lt;0.0001) and CPA (l2fc&lt;-1.4, p&lt;0.0001). <italic>In vitro</italic> studies demonstrated that the PPARG activator rosiglitazone resulted in decreased cell viability in MUC1 and NCI-H295R (p&lt;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&lt;0.05), respectively.</p></sec><sec><title>Outcome</title><p>This therapeutic effect was independent of the actions of ACTH, postulating a promising application of <italic>PPARG</italic> activation in endogenous hypercortisolism.</p></sec>