title: Cholesterol transport, peripheral benzodiazepine receptor, and steroidogenesis in aging Leydig cells.
abstract: The cellular mechanisms responsible for age-related decline in the ability of Leydig cells to produce testosterone are not yet fully understood. The decline in testosterone production could result from a reduction in the Leydig cell enzymatic activities mediating testosterone synthesis, the amount of substrate available for these enzymes, or both. In the present study, we examined the effect of age on a critical early step in the steroidogenic pathway, the transport of cholesterol into mitochondria. Leydig cells were isolated from the testes of young and old Brown Norway rats and incubated with human chorionic gonadotropin (hCG) and the side-chain cleavage cytochrome P450scc inhibitor aminoglutethimide (AMG). Mitochondria were isolated from these cells in the presence of AMG. Upon removal of AMG, the mitochondria from old cells produced 80% less steroid than those from young cells, only a fraction of which could be accounted for by a decrease in P450scc activity. These results suggest that the accumulation of hormonally recruited cholesterol into mitochondria is defective in old Leydig cells. With this in mind, we turned our attention to peripheral benzodiazepine receptor (PBR), a mitochondrial cholesterol-binding protein known to be involved in mediating cholesterol transport. PBR messenger RNA (mRNA) and protein expression were decreased in old cells. Moreover, both the dissociation constant (Kd) and the number of binding sites (Bmax) of the PBR were decreased in the old cells by 50% and 30%, respectively. Taken together, these results suggest that alterations in cholesterol transport and in PBR may play critical roles in age-related decreases in testosterone production in Brown Norway rat Leydig cells.
authors: Department of Cell Biology, Georgetown University School of Medicine, Washington, DC, USA.
authors: Martine
authors: M
authors: Culty
authors: Lindi
authors: L
authors: Luo
authors: Zhi-Xing
authors: ZX
authors: Yao
authors: Haolin
authors: H
authors: Chen
authors: Vassilios
authors: V
authors: Papadopoulos
authors: Barry R
authors: BR
authors: Zirkin
mesh_terms: D000375:Aging / Q000502:physiology*; D000616:Aminoglutethimide / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites / Q000502:physiology; D001692:Biological Transport / Q000502:physiology; D002784:Cholesterol / Q000378:metabolism*; D006063:Chorionic Gonadotropin / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression; D007985:Leydig Cells / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008928:Mitochondria / Q000378:metabolism; D011284:Pregnenolone / Q000096:biosynthesis; D012333:RNA, Messenger / Q000032:analysis; D011869:Radioligand Assay; D051381:Rats; D011914:Rats, Inbred BN; D011963:Receptors, GABA-A / Q000235:genetics / Q000378:metabolism*; D013739:Testosterone / Q000096:biosynthesis*; D014316:Tritium
chemical_list: D006063:Chorionic Gonadotropin; D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D011963:Receptors, GABA-A; D000616:Aminoglutethimide; D014316:Tritium; D013739:Testosterone; D011284:Pregnenolone; D002784:Cholesterol