Regulation of the steroidogenic acute regulatory protein gene expression: present and future perspectives

Abstract

Steroid hormones are synthesized in the adrenal gland, gonads, placenta and brain and are critical for normal reproductive function and bodily homeostasis. The steroidogenic acute regulatory (StAR) protein regulates the rate-limiting step in steroid biosynthesis, i.e. the delivery of cholesterol from the outer to the inner mitochondrial membrane. The expression of the StAR protein is predominantly regulated by cAMP-dependent mechanisms in the adrenal and gonads. Whereas StAR plays an indispensable role in the regulation of steroid biosynthesis, a complete understanding of the regulation of its expression and function in steroidogenesis is not available. It has become clear that the regulation of StAR gene expression is a complex process that involves the interaction of a diversity of hormones and multiple signaling pathways that coordinate the cooperation and interaction of transcriptional machinery, as well as a number of post-transcriptional mechanisms that govern mRNA and protein expression. However, information is lacking on how the StAR gene is regulated in vivo such that it is expressed at appropriate times during development and is confined to the steroidogenic cells. Thus, it is not surprising that the precise mechanism involved in the regulation of StAR gene has not yet been established, which is the key to understanding the regulation of steroidogenesis in the context of both male and female development and function.

Impact of Aging on Steroid Hormone Biosynthesis and Secretion

“…Under normal stress conditions the expression of major AP-1 constituent proteins [382,402] is up-regulated, but in the aging adrenal, the only transcription factor whose expression is increased (rather than decreased) is Jun B [387], a putative repressor of AP-1 function [406][407][408][409][410]. These events suggest that cellular defense against oxidative stress is reduced in aging animals, and the potential impact of this on steroidogenesis becomes even more clear when one realizes that promoter regions of StarD1/StAR and PBR/TSPO genes, the two intracellular molecules which assist in mediating the cholesterol transport process [53,58,59,66,76,81,[417][418][419], contain an AP-1 response element [420,421], and that the proximal AP-1 site in the StarD1/StAR promoter plays a pivotal role in regulating StarD1/StAR gene transcription [420].…”

“…The "acute" production of steroids is dependent upon a hormone-stimulated, rapidly synthesized, cyclohexamide-sensitive and highly labile protein whose function is to transfer cholesterol from outer to inner mitochondrial membranes [53,[61][62][63]. StarD1/StAR is now identified as a putative acute regulatory protein [53,58,59,76,90,417,418]. Recent evidence, however, indicates that StarD1/StAR may also requires participation of a PBR/TSPO multimeric complex in facilitating cholesterol transport from the outer to the inner mitochondrial membrane [75,90,419].…”

Autophagic deficiency is related to steroidogenic decline in aged rat Leydig cells

“…[9][10][11] Androgen is mainly produced by Leydig cells and many enzymes, such as steroidogenic acute regulatory (StAR) protein, cholesterol sidechain cleavage enzyme (P450scc) and 3b-hydroxysteroid dehydrogenase, are involved in regulation of testosterone production. [10][11][12] The functional form of StAR and P450scc are localized in the mitochondrial membrane, and their function is closely related to the mitochondria, furthermore, the StAR protein is an important and rate-limiting enzyme in the regulation of testosterone biosynthesis of Leydig cells. StAR protein expression is predominantly regulated by a cyclic adenosine monophosphate-dependent pathway.…”

“…StAR protein expression is predominantly regulated by a cyclic adenosine monophosphate-dependent pathway. 12 It has been demonstrated that reactive oxygen species (ROS) inhibit StAR expression and testosterone production in Leydig cells through activating p38 mitogen-activated protein kinase or c-Jun. [13][14][15][16] Because mitochondria are the crucial sources of ROS in aerobic eukaryotic cells, androgen deficiency in aged males may be attributed to dysfunctional mitochondria owing to an accumulation of ROS.…”

Maternal Undernutrition Programs Offspring Adrenal Expression of Steroidogenic Enzymes

“…regulation at the hypothalamic-pituitary level, glucocorticoid feedback may occur at the adrenal level, 12,13 mediated by adrenal glucocorticoid receptor (GCR)/mineralocorticoid receptor (MCR). 9,12 Adrenal ACTH receptor (ACTH-R) 14,15 mediates a long-loop feedback axis, by which the hypothalamus/pituitary regulate the expression of steroidogenic enzymes.…”