Transcription controls growth, cell kinetics and cholesterol supply to sustain ACTH responses

Menzies, R. I., Zhao, X., Mullins, L. J., Mullins, J. J., Cairns, C., Wrobel, N., Dunbar, D. R., Bailey, M. A. & Kenyon, C. J.
Endocrine connections
Journal publication date: 

Chronic ACTH exposure (eg Cushings) is associated with adrenal hypertrophy and steroidogenesis. The underlying molecular processes in mice have been analysed by microarray, histological and immunohistochemical techniques. Synacthen infused for 2weeks markedly increased adrenal mass and plasma corticosterone levels. Microarray analysis found greater than 2-fold changes in expression of 928 genes (P<0.001; 397 up, 531 down). These clustered in pathways involved in signalling, sterol/lipid metabolism, cell proliferation/hypertrophy and apoptosis. Signalling genes included some implicated in adenomas but also upregulated genes associated with cyclic AMP and downregulated genes implicated in aldosterone synthesis. Sterol metabolism genes were those promoting cholesterol supply (Scarb1, Sqle, Apoa1) and disposal (Cyp27a1, Cyp7b1). Oil red O staining showed lipid depletion consistent with reduced expression of genes involved in lipid synthesis. Genes involved in steroidogenesis (Star, Cyp11a1, Cyp11b1) were modestly affected (P<0.05; < 1.3-fold). Increased Ki67, Ccna2, Ccnb2, Tk1expression complemented immunohistochemical evidence of a 3-fold change in cell proliferation. Growth arrest genes, Cdkn1a and Cdk1c, which are known to be active in hypertrophied cells, were increased > 4-fold and cross-sectional area of fasciculata cells was 2-fold greater. In contrast, genes associated with apoptosis (eg Casp12, Clu,) were down-regulated and apoptotic cells (Tunel staining) were fewer (P <0.001) and more widely distributed throughout the cortex. In summary, long term steroidogenesis with ACTH excess is sustained by genes controlling cholesterol supply and adrenal mass. ACTH effects on adrenal morphology and genes controlling cell hypertrophy, proliferation and apoptosis suggest the involvement of different cell types and separate molecular pathways.