Cholesterol Side-chain Cleavage Enzyme - Regulation

Regulation

In each steroidogenic cell, the expression of the P450scc system proteins is regulated by the trophic hormonal system specific for the cell type. In adrenal cortex cells from zona fasciculata the expression of the mRNAs encoding all three P450scc proteins is induced by corticotropin (ACTH). The trophic hormones increase CYP11A1 gene expression through transcription factors such as steroidogenic factor 1 (SF-1), by the α isoform of activating protein 2 (AP-2) in the human, and many others. The production of this enzyme is inhibited notably by the nuclear receptor DAX-1.

P450scc is always active, however its activity is limited by the supply of cholesterol in the inner membrane. The supplying of cholesterol to this membrane (from the outer mitochondrial membrane) is thus considered the true rate-limiting step in steroid production. This step is primarily mediated by the steroidogenic acute regulatory protein (StAR or STARD1). Upon stimulation of a cell to make steroid, the amount of StAR available to transfer cholesterol to the inner membrane limits how fast the reaction can go (the acute phase). With prolonged (chronic) stimulation, it is thought that cholesterol supply becomes no longer an issue and that the capacity of the system to make steroid (i.e., level of P450scc in the mitochondria) is now more important.

Corticotropin (ACTH) is a hormone that is released from the anterior pituitary in response to stress situations. A study of the steroidogenic capacity of the adrenal cortex in infants with acute respiratory disease demonstrated that indeed during disease state there is a specific increase in the steroidogenic capacity for the synthesis of the glucocorticoid cortisol but not for the mineralocorticoid aldosterone or androgen DHEAS that are secreted from other zones of the adrenal cortex.