Regulation of the Steroidogenic Acute Regulatory Protein Expression: Functional and Physiological Consequences

Abstract

Steroid hormones are synthesized in steroidogenic cells of the adrenal, ovary, testis, placenta and brain and are essential for normal reproductive function and bodily homeostasis. The rate-limiting and regulated step in steroid biosynthesis is the intramitochondrial transport of cholesterol, a process that is mediated by the steroidogenic acute regulatory (StAR) protein. The importance of StAR has been illustrated by analyses of patients with lipoid congenital adrenal hyperplasia (lipoid CAH), an autosomal recessive disorder that markedly disrupts the synthesis of all gonadal and adrenal steroids. Molecular and physio-pathological analyses have demonstrated that alterations in the StAR gene are the only known cause of lipoid CAH. Furthermore, StAR knockout mice have been generated and display a phenotype that is essentially identical to the human condition. Recent advances in tissue-specific and hormone-induced expression of the StAR protein provide insights into a number of human endocrinological health issues including developmental and reproductive abnormalities. Several factors and processes have been demonstrated to influence StAR expression in steroidogenic cells and there is increasing evidence that a transcription factor-binding site-rich region present in the proximal region of the StAR promoter is highly instrumental in StAR gene expression. In this review we focus on the significant findings that have been made with regards to the regulation of StAR expression and also on the clinical and endocrinological consequences of a non-functioning StAR gene.

Oxidative stress-induced inhibition of adrenal steroidogenesis requires participation of p38 mitogen-activated protein kinase signaling pathway

“…When considering the possibility that COX-2 is a well-established negative modulator of steroid biosynthesis (Nakamura & Sakamoto 2001, Wang et al 2003, Frungieri et al 2006, there is a likely possibility that COX-2 may be involved in the p38 MAPK-mediated downregulation of steroidogenesis. Indeed, it has been recently demonstrated that COX-2 downregulates the gene expression of StAR (Wang et al 2003) (the StAR protein, in concert with several other proteins, especially TSPO facilitate the rate-limiting transfer of cholesterol to the mitochondrial inner membrane where the substrate cholesterol is converted to steroid precursor, pregnenolone by CYP11A1 (P450 scc ; Liu et al 2003, Manna & Stocco 2005). Furthermore, our own unpublished preliminary data suggest that p38 MAPK functions as a suppressor of StAR promoter activity in adrenal and Leydig cell lines (S M Zaidi, unpublished observations).…”

Impact of Aging on Steroid Hormone Biosynthesis and Secretion

“…Among them, the StAR protein possesses all the necessary characteristics of the acute regulator of steroid hormone biosynthesis in steroidogenic cells [58,66], i.e., it is a synthesis specifically induced in the adrenal and gonads in response to tropic hormonal stimulation, is highly labile, and its expression is sensitive to the protein synthesis inhibitor, cycloheximide [58,67]. This candidate protein was initially described by Orme-Johnson and colleagues [64,65].…”

“…Work over the years from this laboratory has shown that the basic problem, at least in aging rats, is that adequate amounts of cholesterol are not available to adrenal (adrenocortical cells) and testis (Leydig cells) for the first step in steroid biosynthesis (i.e., conversion of cholesterol to pregnenolone by the inner mitochondrial membrane-associated side-chain cleavage enzyme system, P450 scc [also designated as CYP11A1]) [25,53,58,66,76,90]. Questions now center on the nature of this defect.…”

“…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].…”

Multilevel regulation of steroid synthesis and metabolism in the bovine placenta

“…As StAR is essential for this step, the level of StAR protein is an important determinant of the availability of cholesterol for steroid synthesis (Stocco and Clark, 1996). The expression of StAR mRNA and its protein is associated with the growth and development of the ster- oidogenic tissues (developmental and tissue-specific regulation) and/or is regulated by trophic hormones, such as adrenocorticotropin (ACTH), LH and follicle stimulating hormone (FSH), and other stimuli (hormonal regulation; Manna and Stocco, 2005). Data on the change in expression of StAR with placental development is reviewed in the next section.…”