Thirty years of StAR gazing. Expanding the universe of the steroidogenic acute regulatory protein

Abstract

The current understanding of the biology, biochemistry and genetics of the steroidogenic acute regulatory protein (StAR) and its deficiency state (lipoid congenital adrenal hyperplasia, lipoid CAH) involves the complex interplay of four areas of study: the acute regulation of steroidogenesis, clinical phenomena in lipoid CAH, the enzymatic conversion of cholesterol to pregnenolone in steroidogenic mitochondria, and the cell biology of StAR. This review traces the origins of these areas of study, describes how they have been woven into an increasingly coherent fabric and tries to explore some remaining loose ends in this ongoing field of endocrine research. Extensive research from multiple laboratories has established that StAR is required for the rapid, abundant steroidal responses of the adrenals and gonads, but all steroidogenic cells, especially the placenta, also have StAR-independent steroidogenesis, whose basis remains under investigation. Lipoid CAH is the StAR knockout of nature whose complex (and unexpected) clinical features are explained by the 'two-hit model', in which StAR-dependent steroidogenesis and StAR-independent steroidogenesis are lost sequentially. StAR is targeted to mitochondria and acts on the outer mitochondrial membrane before being imported via the 'translocase of outer membrane' system and is then inactivated by mitochondrial proteases. A role for the 'translocator protein' (TSPO) has long been proposed, but an essential role for TSPO is excluded by recent transgenic mouse experiments. Crystal structures show that a StAR molecule can bind one cholesterol but does not explain how each StAR molecule triggers the import of hundreds of cholesterol molecules; this is the most pressing area for future research.

Keywords: acute response; cholesterol; congenital lipoid adrenal hyperplasia; mitochondria; steroid.

Figure 1

Sandison’s illustration of the sectioned kidney and adrenal from the patient he reported with ‘lipidosis of the adrenal’. From Sandison (1955), reproduced with permission.

Figure 2

2D gels of mitochondrial proteins showing newly synthesized StAR in cultured mouse MA-10 Leydig cells treated without (panel A) or with (panel B) 1 mM dibutyryl cAMP (dbcAMP) for 6 h. Cells were incubated with ³⁵S-methionine with or without 1 mM dbcAMP. The arrows illustrate the positions of the 30 kDa StAR protein forms. Isoforms 3 and 4 are the phosphorylated forms of isoforms 1 and 2, respectively. Figure courtesy of DM Stocco, from Stocco & Clark (1996), reproduced with permission.

Figure 3

Two-hit model of lipoid CAH. (A) In normal human adrenal cells, cholesterol is primarily derived from low-density lipoproteins, with some endogenous synthesis in the endoplasmic reticulum. The rate-limiting step in steroidogenesis is the flow of cholesterol from the OMM to the IMM, which is facilitated by StAR. (B) Early in lipoid CAH, StAR-independent mechanisms continue to provide some cholesterol, permitting a low level of steroidogenesis. In response to low adrenal steroidogenesis, ACTH secretion increases, stimulating further accumulation of cholesterol and cholesterol esters in lipid droplets. (C) As lipid droplets accumulate, they engorge and damage the cell through physical displacement and by the action of cholesterol auto-oxidation products. The steroidogenic capacity is destroyed, but tropic stimulation continues. In the ovary, follicular cells remain unstimulated and undamaged until puberty when small amounts of estradiol are produced, as in panel B, causing partial feminization, with infertility and hypergonadotropic hypogonadism. Data Bose et al. (1996).

Figure 4

Current model of StAR’s importation into mitochondria; note that the IMM is not shown. Correct protein folding of StAR is facilitated by GRP78 at the MAM. StAR’s mitochondrial leader sequence (amino acids 1–30) then targets it to the mitochondrial protein import machinery on the OMM, while carboxy-terminal domains of StAR interact with VDAC1, VDAC2 and Tom22. StAR’s ‘pause sequence’ (amino acids 31–62) interacts with the Tom40 import channel, slowing its mitochondrial entry and permitting conformational changes (molten globule transition) needed to permit its activity before passing through the import channel. The means by which this complex facilitates cholesterol influx remains unknown. Figure courtesy of HS Bose; data Bose et al. (2023).