Structure, Function, and Regulated Expression of the Steroidogenic Acute Regulatory (StAR) Protein

Abstract

Steroid hormones produced in the adrenals, gonads, and placenta are important regulators of tissue differentiation, development, and homeostasis. The first committed step in the synthesis of these hormones in all tissue types is the conversion of cholesterol into pregnenolone. This reaction is catalyzed by the cytochrome P450 side-chain cleavage enzyme (P450 scc ), located on the matrix side of the inner mitochondrial membrane. This first step in steroidogenesis, which is highly regulated in a temporal and tissue-specific manner, is primarily controlled at the level of cholesterol availability to the inner-mitochondrial matrix rather than at the level of P450 scc enzyme activity. It has been known for decades that the acute regulation of steroid-hormone synthesis in the adrenals and gonads is dependent upon the synthesis of a protein(s) in response to trophic hormones and that this protein is fast-acting (minutes) and functionally short-lived. The recently cloned Steroidogenic Acute Regulatory (StAR) protein appears to be the “labile protein” essential for the acute steroidogenic response. Absence of functional StAR protein causes congenital lipoid adrenal hyperplasia (lipoid CAH), a disease characterized by marked impairment of adrenal and gonadal steroid hormone synthesis. Recent data implicate cAMP-mediated pathways in the regulation of StAR mRNA expression via a mechanism that depends upon the orphan nuclear hormone receptor, steroidogenic factor-1 (SF-1). Additional data suggest that cAMP-mediated pathways stimulate StAR function at the posttranslational level by initiating protein kinase A (PKA)-mediated phosphorylation of StAR. Although StAR has been shown to be imported and processed by mitochondria, this event is not essential to StAR function. It appears that StAR acts on the outer mitochondrial membrane, stimulating sterol desorption from the sterol-rich outer membrane and its transfer to the relatively sterol-poor inner membrane.KeywordsMitochondrial Target SequenceSterol Carrier ProteinSteroidogenic Acute Regulatory ProteinCholesterol Ester HydrolaseSteroidogenic ActivityThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.