Review
A brief history of the search for the protein(s) involved in the acute regulation of steroidogenesis

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Highlights

  • Steroid biosynthesis is controlled by the transfer of cholesterol to the inner mitochondrial membrane.

  • Both the Steroidogenic Acute Regulatory (StAR) and Translocator (TSPO) proteins have been implicated in this process.

  • Knockout of StAR results in a complete inability to synthesize steroids in both humans and mice.

  • Knockout of TSPO has been shown to have no effect on steroid synthesis in mice in two separate laboratories.

  • Previous in vitro studies that demonstrated an essential function for TSPO in steroidogenesis have not been reproducible.

Abstract

The synthesis of steroid hormones occurs in specific cells and tissues in the body in response to trophic hormones and other signals. In order to synthesize steroids de novo, cholesterol, the precursor of all steroid hormones, must be mobilized from cellular stores to the inner mitochondrial membrane (IMM) to be converted into the first steroid formed, pregnenolone. This delivery of cholesterol to the IMM is the rate-limiting step in this process, and has long been known to require the rapid synthesis of a new protein(s) in response to stimulation. Although several possibilities for this protein have arisen over the past few decades, most of the recent attention to fill this role has centered on the candidacies of the proteins the Translocator Protein (TSPO) and the Steroidogenic Acute Regulatory Protein (StAR). In this review, the process of regulating steroidogenesis is briefly described, the characteristics of the candidate proteins and the data supporting their candidacies summarized, and some recent findings that propose a serious challenge for the role of TSPO in this process are discussed.

Introduction

Steroidogenesis is the process by which important steroid hormones are synthesized by specific tissues and cells in the body. Examples of these important steroids are the glucocorticoids that are synthesized in the adrenal cortex, the mineralocorticoids that are synthesized in the adrenal glomerulosa, the ovarian and placental progestins and estrogens, the testicular androgens and several neurosteroids such as pregnenolone, progesterone, 5α-dihydroprogesterone, allopregnanolone and DHEA, that are synthesized in the brain. The adrenal glucocorticoids serve to regulate carbohydrate metabolism and manage stress and the mineralocorticoids are involved in salt balance and the maintenance of blood pressure. Ovarian progesterone and estrogen are involved in the maintenance of female secondary sex characteristics and reproductive function while testicular testosterone is involved in maintaining male secondary sex characteristics and is essential for male fertility. Neurosteroid functions include stimulation of GABAergic responses, modulation of the response of Purkinje cells to excitatory amino acids and the enhancement of memory function. Other tissues and cells have also been reported to have the capacity for de novo steroid synthesis, but the localization of where steroids are synthesized and their respective functions are not the main focus of this review. Rather, this review will concentrate on the manner in which the synthesis of steroid hormones are regulated and the history of the efforts that have been made to uncover the components and the mechanisms involved in this regulation. This history dates back approximately six decades when it was first observed that the synthesis of steroid hormones in vitro could be stimulated with trophic hormones and that this synthesis required the production of a new protein(s), as will be described later in this review. This singular observation formed the basis for what has been a long and most interesting search for the putative regulatory protein(s). We will briefly summarize the early studies that were performed in the search for this regulatory protein(s), the necessary characteristics of the candidates required to perform this function and some of the controversies that have arisen along the way, and indeed, remain to the present time. To be sure, this has been an interesting undertaking by a number of investigators in the field and it would seem safe to say that at this juncture in time, the entire story of what factors are involved in the acute regulation of steroid hormone biosynthesis and how they function is not yet completely understood.

Section snippets

Characteristics of the regulation of steroid hormone biosynthesis

The initial step in steroidogenesis is the conversion of cholesterol to the first steroid formed, pregnenolone, which occurs in all steroidogenic tissues (Miller, 1988, Pescador et al., 1997). This conversion is a result of the action of the cytochrome P450 side-chain cleavage enzyme (P450scc; CYP11A1), that is part of the cholesterol side chain cleavage system that resides on the matrix side of the inner mitochondrial membrane (Farkash et al., 1986). Pregnenolone then exits the mitochondria

The Steroidogenic Acute Regulatory Protein

A candidate protein for the acute regulator of steroidogenesis was first described by Orme-Johnson and her colleagues as an ACTH-induced 30 kDa phosphoprotein in hormone-treated rat and mouse adrenocortical cells, and as an LH-induced protein in rat corpus luteum cells and mouse Leydig cells (Alberta et al., 1989, Epstein and Orme-Johnson, 1991a, Epstein and Orme-Johnson, 1991b, Krueger and Orme-Johnson, 1983, Pon et al., 1986a, Pon et al., 1986b, Pon and Orme-Johnson, 1988). These studies

The Peripheral Benzodiazepine Receptor (PBR)/Translocator Protein (TSPO)

The Peripheral Benzodiazepine Receptor (PBR), whose name was recently changed to the Translocator Protein (TSPO; hereafter referred to as TSPO in this review) was first described in the late 1970s (Gavish et al., 1999). TSPO was demonstrated to have high binding affinity for benzodiazepines but was a distinctly different receptor from the central benzodiazepine receptor, the γ-aminobutyric acid type A receptor/GABAA receptor. Since that time there have been numerous studies involving TSPO that

Controversies in the regulation of cholesterol transfer and steroidogenesis

A brief summary of the studies that have been performed in determining the roles of StAR and TSPO in regulating cholesterol transport to the IMM and thus stimulating steroid biosynthesis is given above. There have been a number of models proposed for the actions of each of these proteins. Some of the models have been challenged as a result of direct experimentation that demonstrated the mechanisms that they proposed to be unlikely, as were the cases with the candidate proteins SCP2 and SAP.

Funding

This work was funded by the National Institutes of Health Grant # HD17481 (DMS), Grant B1-0028 from the Robert A. Welch Foundation (DMS) and startup funds from Cornell University (VS).

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    Present address: Department of Bioscience, Tokyo University of Agriculture, Tokyo 156-8502, Japan.

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