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Cholesterol Transport, Peripheral Benzodiazepine Receptor, and Steroidogenesis in Aging Leydig Cells

LINDI LUO

HAOLIN CHEN

BARRY R. ZIRKIN

From the ^* Division of Hormone Research, Department of Cell Biology, Georgetown University School of Medicine, Washington, DC; and the Division of Reproductive Biology, Department of Biochemistry and Molecular Biology, Johns Hopkins University School of Public Health, Baltimore, Maryland.

Correspondence to: Dr Barry R. Zirkin, Department of Biochemistry and Molecular Biology, John Hopkins University School of Public Health, 615 N Wolfe St, Baltimore, MD 21205-2179 (e-mail: brzirkin{at}jhsph.edu ).

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 P450_scc 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 P450_scc 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.

     Key words: Mitochondria, steroidogenic acute regulatory protein

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