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 PBR ligand, stimulates cholesterol transport and promotes loading of cholesterol to P450scc in vitro, and that its presence is vital for hCG-induced steroidogenesis by Leydig cells. Based on these data and the observations that i) the mitochondrial PBR binding and topography are regulated by hormones; ii) the 18-kDa PBR protein is functionally coupled to the mitochondrial contact site voltage-dependent anion channel protein; iii) the 18-kDa PBR protein is a channel for cholesterol, as shown by molecular modeling and in vitro reconstitution studies; iv) targeted disruption of the PBR 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 PBR ligand binding; and vi) in vivo reduction of adrenal PBR expression results in reduced circulating glucocorticoid levels, we conclude that PBR is an indispensable element of the steroidogenic machinery.
Papadopoulos
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V
Department of Cell Biology, Georgetown University Medical Center, Washington, DC 20007, USA.
Amri
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H
Boujrad
N
N
Cascio
C
C
Culty
M
M
Garnier
M
M
Hardwick
M
M
Li
H
H
Vidic
B
B
Brown
A S
AS
Reversa
J L
JL
Bernassau
J M
JM
Drieu
K
K
D000818:Animals; D001665:Binding Sites; D001692:Biological Transport; D002352:Carrier Proteins / Q000187:drug effects / Q000378:metabolism / Q000494:pharmacology; D002462:Cell Membrane / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism*; D006063:Chorionic Gonadotropin / Q000494:pharmacology; D000242:Cyclic AMP / Q000494:pharmacology; D026261:Diazepam Binding Inhibitor; D005445:Flunitrazepam / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D008954:Models, Biological; D008958:Models, Molecular; D009154:Mutation; D011487:Protein Conformation; D011963:Receptors, GABA-A / Q000737:chemistry* / Q000187:drug effects / Q000502:physiology*; D013256:Steroids / Q000378:metabolism*
D002352:Carrier Proteins; D006063:Chorionic Gonadotropin; D026261:Diazepam Binding Inhibitor; D011963:Receptors, GABA-A; D013256:Steroids; D005445:Flunitrazepam; D002784:Cholesterol; D000242:Cyclic AMP