Adrenocortical Responsiveness to Adrenocorticotropin: StAR Is Ascendant

Abstract

The circadian rhythm in glucocorticoid secretion by the adrenal cortex was long considered to be a product and direct reflection of the circadian rhythm of ACTH secretion by the anterior pituitary. However, data have accumulated for several years indicating that changes in circulating ACTH cannot fully explain the adrenal rhythm, and under many conditions there is a dissociation between ACTH and glucocorticoids (1). The circadian rhythm in plasma glucocorticoid concentration is extremely robust, and in many species has a much greater amplitude than the ACTH rhythm (2). In rats after hypophysectomy, the corticosteroid rhythm persists and exhibits 3-fold differences in response to exogenous ACTH, depending on the time of day (3, 4); and in capuchin monkeys, markedly rhythmical cortisol secretion continues after ACTH suppression with dexamethasone (5). Additional findings of nycthemeral differences in adrenal responsiveness to ACTH (6, 7), the ability of a restricted feeding schedule to alter those rhythms (8), and the demonstration that innervation of the adrenal cortex via the splanchnic nerve plays a major role in regulation of circadian glucocorticoid secretion (2, 9) have all contributed to our understanding that stimulation of adrenal steroidogenesis is subject to a number of potent influences in addition to ACTH. Circadian clocks, both the central rhythm generator in the suprachiasmatic nuclei of the hypothalamus and the peripheral oscillators that have been discovered in multiple mammalian tissues, regulate temporal output via interlocking transcriptional/ translational feedback loops involving the core clock genes Per1-2, Cry1-2, Clock, and Bmal1, and their protein products (10). In recent years the molecular machinery necessary for generation of circadian rhythms has been found in the adrenal cortex of rodents and primates, and the adrenal clock of capuchin monkeys maintains a circadian rhythm in vitro (11). These findings suggest that this molecular adrenal clock may also be among the modulators of the steroidogenic response to ACTH. In this issue of Endocrinology, Torres-Farfan et al. (12) have demonstrated that in the capuchin monkey (Cebus apella) adrenal cortex, an antisense knockdown of the expression of the adrenal clock protein cryptochrome 2 (CRY2) blocks the adrenal’s steroidogenic response to stimulation by ACTH. Another recent study showed that expressionofadifferent canonical clockprotein, BMAL1, is necessary for steroidogenesis in the Y-1 immortalized mouse adrenocortical cell line (13). In addition, a transgenic mouse line in which a part of the BMAL1 coding region was expressed in an antisense orientation under tissue-specific control failed to express rhythms of corticosteroid synthesis and secretion when the animals were maintained in constant darkness. Because steroidogenic cells store very little steroid, acute increases in secretion in response to a stimulus require rapid synthesis of new steroid, and the rate-limiting step of transfer of cholesterol across the mitochondrial membranes is dependent on de novo protein synthesis (14). Acute steroidogenesis was found to be accompanied by the synthesis of a phosphoprotein (15) that occurs much more rapidly than ACTH-elicited synthesis of steroidogenic enzymes. The protein was cloned and named steroidogenic acute regulatory protein (StAR) (16). In the aforementioned studies in which adrenal steroidogenic responses to ACTH were found to be dependent on clock proteins and in several other investigations of factors observed to modulate steroidogenesis, the effects were achieved at least partly by alteration of StAR transcription. StAR is expressed only in steroidogenic tissues [adrenal cortex, testes, ovaries, placenta, and brain (17)] and mediates the transfer of mobilized cholesterol from the outer to the inner mitochondrial membrane, the site of the first enzymatic step in steroidogenesis, side chain cleavage of cholesterol to form pregnenolone. The clinical consequence of dysfunctional StARs resulting from gene mutations is congenital lipoid adrenal hyperplasia (18). The absence of functional StAR results in a roughly 85% loss of steroidogenesis that elicits compensatory ACTH secretion and subsequent cellular damage from massive accumulation in lipid droplets of esterified cholesterol that cannot be transported into mitochondria (14).