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

Abstract

Current understanding of the biology, biochemistry and genetics of the steroidogenic acute regulatory protein (StAR) and its deficiency state (congenital lipoid 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. Abundant research from multiple laboratories establishes that StAR is required for the rapid, abundant steroidal responses of the adrenals and gonads, but all steroidogenic cells, especially the placenta, 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 and StAR-independent steroidogenesis are sequentially lost. StAR is targeted to mitochondria and acts on the outer mitochondrial membrane before being imported via the 'translocase of outer membrane' (Tom) system, and 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 on cholesterol molecules; this is the most pressing area for future research.