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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.
Although specific binding of PBR ligands was reported to be present on cell membranes (Weissman et al, 1990), copious studies associated these receptors with the outer mitochondrial membranes and linked them to one or more mechanisms that are involved in cholesterol trafficking. Because the transfer of cholesterol to P450sec for conversion to pregnenolone is the limiting step in hormone-induced steroid biosynthesis, there is no need to emphasize the relevance of PBR in this process. The concentration of the final product of this pathway in testicular tissue (ie, testosterone), is controlled by the trophic hormones luteinizing hormone (LH) and follicle-stimulating hormone (FSH). It turns out that in the testis, PBR density is subject to both LH/FSH and testosterone influence. Thus, elevation of the levels of the latter hormone caused a marked decrease in the binding capacity of [3H]PK 11195 (Amiri et al, 1991). However, whereas these observations seem to portray a clear picture of regulation and feedback mechanisms, the picture is muddied due to findings reported by the same authors demonstrating that the antiandrogen cyproterone mimics the effects of testosterone.
The article by Culty et al in this issue of the Journal of Andrology reports on reductions in PBR messenger RNA and protein expression as well as a decrease in the binding capacity of [3H]PK 11195, observed in isolated Leydig cells from aging rats. The latter finding is in accord with an earlier publication describing the ontogenesis of this ligand binding to rat testis (Mercer et al, 1992). These changes in receptor characteristics were correlated to diminution of cholesterol transport from the outer to the inner mitochondrial membrane in old Leydig cells. Lower cholesterol transport is translated into diminished testosterone output by steroidogenic enzymes. Moreover, it is also notable that unlike other endocrine organs (eg, adrenal gland), the density of [3H]PK 11195 binding sites in the testis exhibited developmental alterations, culminating in a distinct decline at the age of 24 months. Because cholesterol transport is of the utmost importance, another candidate for its trafficking should be discussed, namely, steroidogenic acute regulatory (StAR) protein. There is no winner in the contest between PBR and StAR for physiological supremacy yet, and in this respect, the paper by West et al (2001) is of particular interest. According to the proposed model by West et al, cholesterol-loaded StAR associates with PBR at the outer mitochondrial membrane. Nevertheless, although a recipe for collaboration was offered, evidence for actual cholesterol transfer among the two entities was not presented.
Notwithstanding that remarkable effort was invested in a search for the roles played by the 3 subunits of PBR, basic questions such as possible interactions between subunits are unanswered. Furthermore, an additional topic that clearly deserves attention is the physiological significance of the putative endogenous ligand, diazepam binding inhibitor (DBI). Endozepine could modulate cholesterol transfer by PBR or affect the proposed interaction between StAR and PBR; other actions of this peptide cannot be excluded at this stage. Studies using PBR-knockout mice, for example, could shed light on questions such as the implication of PBR and hCG as partners that act through a shared pathway. Although current knowledge offers reasonable clues as to the function of PBR in steroidogenesis, no categorical definition is available. If only for their phenomenal abundance in endocrine organs, they should get our utmost attention.
References
Amiri Z, Weizman R, Katz Y, Burstein O, Edoute Y, Lochner A, Gavish M. Testosterone and cyproterone acetate modulate peripheral but not central benzodiazepine receptors in rats. Brain Res. 1991; 553: 155 -158.[Medline]
Mercer KA, Weizman R, Gavish M. Ontogenesis of peripheral benzodiazepine receptors: demonstration of selective up-regulation in rat testis as a function of maturation. J Recept Res. 1992; 12: 413 -425.[Medline]
Ritta MN, Campos MB, Calandra RS. Effect of GABA and benzodiazepines on testicular androgen production. Life Sci. 1987;40: 791 -798.[Medline]
Weissman BA, Elson HF, Kaplan D, Newman AH. Presence of peripheral benzodiazepine binding sites on primary rat skeletal fibroblasts, Eur J Pharmacol. 1990; 187: 369 -375.[Medline]
West LA, Horvat RD, Roess DA, Barisas BG, Juengel JL, Niswender GD.
Steroidogenic acute regulatory protein and peripheral-type benzodiazepine
receptor associate at the mitochondrial membrane.
Endocrinology.
2001; 142:
502
-505.
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