Peripheral benzodiazepine receptor in cholesterol transport and steroidogenesis

Steroidogenesis begins with the metabolism of cholesterol to pregnenolone by the inner mitochondrial membrane cytochrome P450 side-chain cleavage (P450scc) enzyme. The rate of steroid formation, however, depends on the rate of cholesterol transport from intracellular stores to the inner mitochondrial membrane and loading of P450scc with cholesterol. In previous in vitro studies, we demonstrated that a key element in the regulation of cholesterol transport is the mitochondrial peripheral-type benzodiazepine receptor (PBR). We also showed that the polypeptide diazepam binding inhibitor (DBI), an endogenous PER ligand, stimulates cholesterol transport and promotes loading of cholesterol to P450scc in vitro, and that its presence is vital for hCG-induced steroido-genesis by Leydig cells. Based on these data and the observations that ii the mitochondrial PER binding and topography are regulated by hormones; ii) the 18-kDa PER protein is functionally coupled to the mitochondrial contact sire voltage-dependent anion channel protein; iii) the 18-kDa PER protein is a channel for cholesterol, as shown by molecular modeling and in vitro reconstitution studies; iv) targeted disruption of the PER gene in steroidogenic cells dramatically reduces the ability of the cells to transport cholesterol in the mitochondria and produce steroids: v) endocrine disruptors, with known anisteroidogenic effect, inhibit PER ligand binding; and vi) in vivo reduction of adrenal PER expression results in reduced circulating glucocorticoid levels, we conclude that PER is an indispensable element of the steroidogenic machinery. (C) 1997 by Elsevier Science Inc.