| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Perspectives and Editorials |
Culty M, Luo L, Yao Z, Chen H, Papadopoulos V, Zirkin B.
Cholesterol transport, peripheral benzodiazepine receptor, and steroidogenesis
in aging Leydig cells. J Androl.
2002
;23:439–447.
The modern man may prefer not to resort to philosophy in his older age, but may instead appreciate the psychological and physiological benefits of a youthful dose of testosterone. To be sure, there is a burgeoning industry devoted to androgen replacement therapy, the consequences of which are a subject of active debate in the current literature. The article by Culty et al in this issue of Journal of Andrology addresses the more fundamental question: What are the cellular mechanisms underlying the decrease in testosterone production that accompanies aging?
This article from Dr Zirkin's laboratory represents the next logical step in their analysis of age-related changes in steroidogenesis in Leydig cells from Brown Norway rats. The Brown Norway rat is an excellent model for studying aging in males because it presents primary testicular deficits similar to that observed in humans. Leydig cell numbers do not change with aging; instead, the steroidogenic capacity of Leydig cells in old individuals declines. Previous work from the Zirkin group has established that the activity, protein, and messenger RNA level of P450scc and each of the enzymatic reactions distal to this mitochondrial step are reduced in aged Leydig cells. Steroidogenic acute regulatory protein (StAR) is responsible for mediating the first hormonally regulated and rate-limiting step in testosterone biosynthesis, the transfer of cholesterol from the outer to the inner mitochondrial membrane to P450scc, which catalyzes the first enzymatic step in the pathway (Stocco, 2001). Zirkin's group, as well as Azhar and coworkers (Leers-Sucheta et al, 1999) have shown that Leydig cell StAR expression decreases with aging. Although the preponderance of evidence supports the essential role that StAR plays in mediating the acute and hormonally regulated transfer of cholesterol into the mitochondrion, it is clear that StAR alone cannot account for cholesterol transfer across the mitochondrial membranes, especially under basal or unstimulated conditions. Moreover, considerable controversy exists as to the molecular mechanisms through which StAR mediates hormonally stimulated cholesterol transfer (for a review see Christenson and Strauss, 2000). The peripheral benzodiazepine receptor (PBR) is a high-affinity mitochondrial cholesterol-binding protein that also participates in cholesterol transport to the steroidogenic pathway. How StAR and PBR may interact, or how they both participate in cholesterol transport in steroidogenic tissues remains a subject of some controversy. It is evident, however, that both StAR and PBR participate in and are essential to the process of substrate delivery across the mitochondrial membranes (Waterman, 1998).
Because the rate-limiting step of steroidogenesis has been shown to be the transport of cholesterol to P450scc, alterations in cholesterol availability to this first enzymatic step in the pathway would affect the capacity for testosterone biosynthesis. The report by Zirkin and coworkers assesses the availability of cholesterol stores for steroidogenesis in old vs. young Leydig cells, and is the first study that examines age-related changes in PBR expression and activity.
To assess availability of cholesterol and to determine whether alterations in the cholesterol pool during aging may account for decreased steroidogenic response in old Leydig cells, the P450scc inhibitor aminoglutethimide (AMG) was employed. Leydig cells were stimulated with human chorionic gonadotropin and treated with AMG, which led to an accumulation of hormonally recruited cholesterol into mitochondrial membranes. This approach provides an indirect measure of the steroidogenic cholesterol pool. After removal of AMG and reactivation of P450scc, there was a significant decrease in mitochondrial steroidogenesis, far greater than could be accounted for by the overall decrease in P450scc in Leydig cell mitochondria from the older rats. This observation indicated that there was a reduction in the transport of cholesterol into the mitochondria in old Leydig cells. This could be due to a decrease in the available cholesterol pool, or to a defect in the cholesterol transport machinery. To test the second possibility the expression and function of PBR was examined. The transfer of cholesterol across the mitochondrial membranes is a complex process. The mechanism through which PBR participates as a component of the cholesterol transfer machinery is not fully understood. PBR is an 18-kd outer mitochondrial membrane protein that was discovered as a peripheral binding site for benzodiazepines, and is distinct from the neurotransmitter receptors. PBR isoquinoline-binding activity provides a measure of its cholesterol transfer activity. In this report by Culty et al, PBR messenger RNA and protein levels were reduced in Leydig cells from old rats. In addition, Zirkin and coworkers also determined, in receptor binding assays, that isoquinoline PK 11195 binding to PBR was decreased, indicating that the activity of PBR was reduced as a result of aging. The use of a radiolabeled isoquinoline binding assay provides an independent and highly specific assay for PBR activity, independent of changes in its protein expression.
The senescence of Leydig cell steroidogenic function with aging involves a host of factors. The elegant study from the Zirkin group clearly shows that changes in cholesterol transport into the steroidogenic pathway contribute in a significant way to the age-related reduction in steroidogenic capacity. Their demonstration that a reduction in PBR expression and receptor binding activity parallels this reduction identifies another component of the steroidogenic apparatus that declines with age, and it reinforces the important role that PBR plays in the process. The present data add to a further understanding of one Socratic dilemma, and proves that there is more than a Platonic relationship between StAR and PBR.
References
Christenson LK, Strauss JF. Steroidogenic acute regulatory protein (StAR) and the intramitochondrial translocation of cholesterol. Biochim Biophys Acta. 2000; 1529: 175 -187.[Medline]
Hollander N, Hollander VT. The microdetermination of testosterone in human spermatic vein blood. J Clin Endocrinol Metab. 1958;18: 966 -971.
Leers-Sucheta S, Stocco DM, Azhar S. Down-regulation of steroidogenic acute regulatory (StAR) protein in rat Leydig cells: implications for regulation of testosterone production during aging. Mech Ageing Dev. 1999; 107: 197 -203.[Medline]
Stocco DM. StAR protein and the regulation of steroid hormone biosynthesis. Annu Rev Physiol. 2001; 63: 193 -213.[Medline]
Waterman MR. Steroidogenesis, StAR and PBR: is there light at the end of the tunnel? [comment]. Proc Soc Exp Biol Med. 1998; 217: 121 -122.[Medline]
| ||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
