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Regulation of Leydig Cell Cholesterol Metabolism

  • Salman Azhar
  • Eve Reaven
Part of the Contemporary Endocrinology book series (COE)

Abstract

Steroidogenic tissues have special requirements for cholesterol, which is used as a substrate for tissue specific steroid biosynthesis. Because of this, all steroidogenic tissues, including Leydig cells, have evolved multiple cholesterol delivery pathways and an efficient intracellular cholesterol transport system to ensure constant supply and adequate availability of cholesterol. There are four potential sources, which could contribute to the putative “cholesterol pool” needed for steroidogenesis: (a) de novo synthesized cholesterol, (b) stored cholesteryl esters, (c) exogenous lipoprotein-supplied cholesterol, and (d) plasma membrane-derived cholesterol. Among these, the cholesterol-rich plasma lipoproteins are often the most utilized source of cholesterol for steroid production. Cells acquire lipoprotein-cholesterol both by classic LDL receptor-mediated endocytosis and by selective uptake pathways. In the latter case, lipoprotein cholesteryl ester is selectively internalized without the concomitant uptake and lysosomal degradation of the entire lipoprotein particle. This bulk cholesterol delivery pathway is mediated by a scavenger receptor class B, type-I protein, which is highly expressed and hormonally regulated in steroidogenic cells. In addition to an adequate supply of intracellular cholesterol, steroidogenic cells also require efficient and controlled delivery of cholesterol to outer mitochondrial membranes, and subsequently, to inner mitochondrial membranes for P450scc catalyzed pregnenolone production—the precursor product for all steroids. Although, the exact steps involved in intracellular cholesterol transport to the outer mitochondrial membrane are not yet defined, it appears that vesicular/nonvesicular (through carrier protein) transport processes and interactions between mitochondria, and lipid droplets are probably involved. Two highly studied proteins, peripheral-type benzodiazepine receptor, and steroidogenic acute regulatory protein/steroidogenic acute regulatory protein D1, may function individually, or in concert, to subsequently facilitate the transfer of cholesterol from the outer to inner mitochondrial membranes—the rate-limiting step in steroidogenesis. The present chapter highlights the current understanding of these critical events in Leydig cells; i.e., the acquisiton, intracellular processing, transport, and utilization of cholesterol as the substrate for testosterone production.

Key Words

Cholesterol transport cholesterol transport proteins cholesteryl esters endocytic pathway HDL LDL LDL-receptor lipid droplets selective pathway SR-BI steroidogenesis 

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References

  1. 1.
    Christensen AK. Leydig cells. In: Hamilton DW, Greep RO eds. Handbook of Physiology, Washington DC: American Physiological Society, 1975;57–94.Google Scholar
  2. 2.
    Zirkin BR, Ewing LL, Kromann N, Cochran RC. Testosterone secretion by rat, rabbit, guinea pig, dog, and hamster testes perfused in vitro: correlation with Leydig cell ultrastructure. Endocrinology 1980;107:1867–1874.PubMedGoogle Scholar
  3. 3.
    Lunstra DD, Ford JJ, Christenson RK, Allrich RD. Changes in Leydig cell ultrastructure and function during pubertal development in the boar. Biol Reprod 1986;34:145–158.PubMedGoogle Scholar
  4. 4.
    Hou JW, Collins DC, Schleicher RL. Sources of cholesterol for testosterone biosynthesis in murine Leydig cells. Endocrinology 1990;2047–2055.Google Scholar
  5. 5.
    Lejeune H, Skalli M, Sanchez P, Avallet O, Saez JM. Enhancement of testosterone secretion by normal adult human Leydig cells by co-culture with enriched preparations of normal adult human Sertoli cells. Int J Androl 1993;16:27–34.PubMedGoogle Scholar
  6. 6.
    Anbalagan M, Sriraman V, Rao AJ. Isolation and characterization of Leydig cells from adult bonnet monkeys (Macaca radiata): evidence for low steroidogenic capacity in monkey Leydig cells in contrast to rat Leydig cells. J Endocrinol 2003;175–182.Google Scholar
  7. 7.
    Payne AH, Hales DB. Overview of steroidogenic enzymes in the pathway from cholesterol to active steroid hormones. Endocr Res 2004;25:947–970.Google Scholar
  8. 8.
    Jefcoate CR, McNamara BC, Artemenko I, Yamazaki T. Regulation of cholesterol movement to mitochondrial cytochrome P450scc in steroid hormone synthesis. J Steroid Biochem Mol Biol 1992;743:751–767.Google Scholar
  9. 9.
    Stocco DM. Intramitochondrial cholesterol transfer. Biochim Biophys Acta 2000;1486:184–197.PubMedGoogle Scholar
  10. 10.
    Parker KL, Schimmer BP. Transcriptional regulation of the genes encoding the cytochrome P-450 steroid hyroxylases. Vitam Horm 1995;51:339–370.PubMedGoogle Scholar
  11. 11.
    Waterman MR, Keeney DS. Signal transduction pathways combining peptide hormones and steroidogenesis. Vitam Horm 1996;52:129–148.PubMedGoogle Scholar
  12. 12.
    Cooke BA. Signal transduction involving cyclic AMPdependent and cyclic AMP-independent mechanisms in the control of steroidogenesis. Mol Cell Endocrinol 1999; 151:25–35.PubMedGoogle Scholar
  13. 13.
    Stocco DM, Wang X, Jo Y, Manna PR. Multiple signaling pathways regulating steroidogenesis and StAR expression: More complicated than we thought. Mol Endocrinol 2005; 19:2647–2659.PubMedGoogle Scholar
  14. 14.
    Saez JM. Leydig cells: Endocrine, paracrine, and autocrine regulation. Endocr Rev 1994;15:574–626.PubMedGoogle Scholar
  15. 15.
    Hales DB. Testicular macrophage modulation of Leydig cell steroidogenesis. J Reprod Immunol 2002;57:3–18.PubMedGoogle Scholar
  16. 16.
    Haider SG. Cell biology of Leydig cells in testis. Int Rev Cytol 2004;233:181–241.PubMedGoogle Scholar
  17. 17.
    Gwynne JT, Strauss JF III. The role of lipoproteins in steroidogenesis and cholesterol metabolism in steroidogenic glands. Endocr Rev 1982;3:299–329.PubMedGoogle Scholar
  18. 18.
    Pedersen RC. Cholesterol biosynthesis, storage, and mobilization in steroidogenic organs. In: Yeagle PL ed. Biology of Cholesterol. Boca Raton, FL: CRC Press Inc., 1988;39–69.Google Scholar
  19. 19.
    Azhar S, Reaven P. Scavenger receptor Class BI and selective cholesteryl ester uptake: partners in the regulation of steroidogenesis. Mol Cell Endocrinol 2002;195:1–26.PubMedGoogle Scholar
  20. 20.
    Azhar S, Leers-Sucheta S, Reaven E. Cholesterol uptake in adrenal and gonadal tissues: the SR-BI and “selective” pathway connection. Front Biosci 2003;8:S998–S1029.PubMedGoogle Scholar
  21. 21.
    Soccio RE, Breslow JL. Intracellular cholesterol transport. Arterioscler Thromb Vasc Biol 2004;24:1150–1160.PubMedGoogle Scholar
  22. 22.
    Spady DK, Dietschy JM. Sterol synthesis in vivo in 18 tissues of the squirrel monkey, guinea pig, rabbit, hamster, and rat. J Lipid Res 1983;24:303–315.PubMedGoogle Scholar
  23. 23.
    Brown MS, Goldstein JL. A receptor-mediated pathway for cholesterol homeostasis. Science 1986;232:34–47.PubMedGoogle Scholar
  24. 24.
    Rigotti A, Miettinen HE, Krieger M. The role of the highdensity lipoprotein receptor SR-BI in the lipid metabolism of endocrine and other tissues. Endocr Rev 2003;357–387.Google Scholar
  25. 25.
    Kraemer FB, Shen W-J. Hormone-sensitive lipase: control of intracellular tri-(di-) acylglycerol and cholesteryl ester hydrolysis. J Lipid Res 2002;43:1585–1594.PubMedGoogle Scholar
  26. 26.
    Freeman DA. Plasma membrane cholesterol: removal and insertion into the membrane and utilization as substrate for steroidogenesis. Endocrinology 1989;2527–2534.Google Scholar
  27. 27.
    Pörn MI, Tenhunen J, Slotte JP. Increased steroid hormone secretion in mouse Leydig tumor cells after induction of cholesterol translocation by sphingomyelin degradation. Biochim Biophys Acta 1991;1093:7–12.PubMedGoogle Scholar
  28. 28.
    Reaven E, Zhan L, Nomoto A, Leers-Sucheta S, Azhar S. Expression and microvillar localization of scavenger receptor class B, type I (SR-BI) and selective cholesteryl ester uptake in Leydig cells from rat testis. J Lipid Res 2000;41:343–356.PubMedGoogle Scholar
  29. 29.
    Schroepfer GJ Jr. Sterol biosynthesis. Annu Rev Biochem 1982;51:555–585.PubMedGoogle Scholar
  30. 30.
    Rudney H, Sexton RC. Regulation of cholesterol biosynthesis. Annu Rev Nutr 1986;6:245–272.PubMedGoogle Scholar
  31. 31.
    Ness GC, Chambers CM. Feedback and hormonal regulation of hepatic 3-hydroxy-3-methylglutaryl Coenzyme A reductase: the concept of cholesterol buffering capacity. Proc Soc Exp Biol Med 2000;224:8–19.PubMedGoogle Scholar
  32. 32.
    Goldstein JL, Brown MS. Regulation of the mevalonate pathway. Nature 1990;343:425–430.PubMedGoogle Scholar
  33. 33.
    Hampton RY. Proteolysis and sterol regulation. Annu Rev Cell Dev Biol 2002;18:345–378.PubMedGoogle Scholar
  34. 34.
    Horton JD, Goldstein JL, Brown MS. SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J Clin Invest 2002;109:1125–1131.PubMedGoogle Scholar
  35. 35.
    Kennelly PJ, Rodwell VW. Regulation of 3-hydroxy-3methylglutaryl coenzyme A reductase by reversible phosphorylation-dephosphorylation. J Lipid Res 1985;26:903–914.PubMedGoogle Scholar
  36. 36.
    Jeon H, Blacklow SC. Structure and physiologic function of the low-density lipoprotein receptor. Annu Rev Biochem 2005;74:535–562.PubMedGoogle Scholar
  37. 37.
    Chen WJ, Goldstein JL, Brown MS. NPXY, a sequence often found in cytoplasmic tails, is required for coated pit-mediated internalization of the low density lipoprotein receptor. J Biol Chem 1990;265:3116–3123.PubMedGoogle Scholar
  38. 38.
    Chang T-Y, Reid PC, Sugii S, Ohgami N, Cruz JC, Chang CCY. Niemann-Pick type C disease and intracellular cholesterol trafficking. J Biol Chem 2005;280:20,917–20,920.Google Scholar
  39. 39.
    Neufeld EB, Cooney AM, Pitha J, et al. Intracellualr trafficking of cholesterol monitored with a cyclodextrin. J Biol Chem 1996;271:21,604–21,613.Google Scholar
  40. 40.
    Millard EE, Srivastava K, Traub LM, Schaffer JE, Ory DS. Niemann-Pick type C1 (NPC1) overexpression alters cellular cholesterol homeostasis. J Biol Chem 2000;275: 38,445–38,451.Google Scholar
  41. 41.
    Wojtanik KM, Liscum L. The transport of low density-derived cholesterol to the plasma membrane is defective in NPC1 cells. J Biol Chem 2003;278:14,850–14,856.Google Scholar
  42. 42.
    Zhang M, Liu P, Dwyer NK, et al. MLN64 mediates mobilization of lysosomal cholesterol to steroidogenic mitochondria. J Biol Chem 2002;277:33,300–33,310.Google Scholar
  43. 43.
    Bose HS, Whittal RM, Huang MC, Baldwin MA, Miller WL. N-218 MLN64, a protein with StAR-like steroidogenic activity, is folded and cleaved similarly to StAR. Biochemistry 2000;39:1l,722–11,731.Google Scholar
  44. 44.
    Connelly MA, Williams DL. SR-BI and cholesterol uptake into steroidogenic cells. Trends Endocrinol Metab 2003; 14:467–472.PubMedGoogle Scholar
  45. 45.
    Webb NR, Connell PM, Graf GA, et al. SR-BII, an isoform of the scavenger receptor BI containing an alternate cytoplasmic tail, mediates lipid transfer between high density lipoprotein and cells. J Biol Chem 1998;273:15,241–15,248.Google Scholar
  46. 46.
    Azhar S, Nomoto A, Reaven E. Hormonal regulation of adrenal microvillar channel formation. J Lipid Res 2002;43: 861–871.PubMedGoogle Scholar
  47. 47.
    Reaven E, Nomoto A, Leers-Sucheta S, Temel R, Williams DL, Azhar S. Expression and microvillar localization of scavenger receptor, class B, type I (a high density lipoprotein receptor) in luteinized and hormone-desensitized rat ovarian models. Endocrinology 1998;139:2847–2856.PubMedGoogle Scholar
  48. 48.
    Rigotti A, Edelman ER, Seifert P, et al. Regulation of adrenocorticotropic hormone of the in vivo expression of scavenger receptor class B type I (SR-BI), a high density lipoprotein receptor, in steroidogenic cells of the murine adrenal gland. J Biol Chem 1996;271:33,545–33,549.Google Scholar
  49. 49.
    Maxfield FR, Wüstner D. Intracellular cholesterol transport. J Clin Invest 2002;110:891–898.PubMedGoogle Scholar
  50. 50.
    Murphy DJ. The biogenesis and functions of lipid bodies in animals, plants and microorganisms. Prog Lipid Res 2001; 40:325–338.PubMedGoogle Scholar
  51. 51.
    Chang TY, Chang CC, Cheng D. Acyl-coenzyme Axholesterol acyltransferase. Annu Rev Biochem 1997;66:613–638.PubMedGoogle Scholar
  52. 52.
    Buhman KF, Accad M, Farese RV. Mammalian acyl-CoAxholesterol acyltransferases. Biochim Biophys Acta 2000;1529:142–154.PubMedGoogle Scholar
  53. 53.
    Londos C, Brasaemle DL, Schultz CJ, Segrest JP, Kimmel AR. Perilipins, ADRP, and other proteins that associate with intracellular neutral lipid droplets in animal cells. Semin Cell Dev Biol 1999;10:51–58.PubMedGoogle Scholar
  54. 54.
    Miura S, Gan J-W, Brzostowski J, Parisi MJ, Schultz CJ, Landos C, Oliver B, Kimmel AR. Functional conservation for lipid storage droplet association among perilipin, ADRP, TIP47 (PAT)-related proteins in mammals, Drosophila, and Dictyostelium. J Biol Chem 2002;277:32,253–32,257.Google Scholar
  55. 55.
    Wolins NE, Quaynor BK, Skinner JR, Schoenfish MJ, Tzekov A, Bickel P. S3-12, adipophilin, and TIP47 package lipid in adipocytes. J Biol Chem 2005;280:19,146–19,155.Google Scholar
  56. 56.
    Brasaemle DL, Barber T, Wolins NE, Serrero G, Blanchette-Mackie EJ, Londos C. Adipose differentiation-related protein is an ubiquitously expressed lipid storage droplet-association protein. J Lipid Res 1997;38:2249–2263.PubMedGoogle Scholar
  57. 57.
    Tansey JT, Sztalryd C, Hlavin EM, Kimmel AR, Londos C. The central role of perilipin A in lipid metabolism and adipocyte lipolysis. IUBMB Life 2004;56:379–385.PubMedGoogle Scholar
  58. 58.
    Morris MD, Chaikoff IL. 1959. The origin of cholesterol in liver, small intestine, adrenal gland, and testis of the rat: dietary versus endogenous contributions. J Biol Chem 1959;234:1095–1097.PubMedGoogle Scholar
  59. 59.
    Andersen JM, Dietschy JM. Relative importance of high and low density lipoproteins in the regulation of cholesterol synthesis in the adrenal gland, ovary, and testis of the rat. J Biol Chem 1978;253:9024–9032.PubMedGoogle Scholar
  60. 60.
    Charreau EH, Calvo JC, Nozu K, Pignataro O, Catt KJ, Dufau ML. Hormonal modulation of 3-hydroxy-3-methylglutaryl Coenzyme A reductase activity in gonadotropin-stimulated and-desensitized testicular Leydig cells. J Biol Chem 1981; 12,719–12,724.Google Scholar
  61. 61.
    Azhar S, Menon KMJ. Receptor-mediated gonadotropin action in gonadal tissues: Relationship between blood cholesterol levels and gonadotropin stimulated steroidogenesis in isolated rat Leydig and luteal cells. J Steroid Biochem 1982;16:175–184.PubMedGoogle Scholar
  62. 62.
    Hedger MP, Risbridger GP. Effect of serum and serum lipoproteins on testosterone production by adult rat Leydig cells in vitro. J Steroid Biochem Mol Biol 1992;43:581–589.PubMedGoogle Scholar
  63. 63.
    Freeman DA, Ascoli M. Studies on the source of cholesterol used for steroid biosynthesis in cultured Leydig tumor cells. J Biol Chem 1982;257:14,231–14,238.Google Scholar
  64. 64.
    Ascoli M. Effects of hypocholesterolemia and chronic hormonal stimulation on the sterol and steroid metabolism in a Leydig cell tumor. J Lipid Res 1981;22:1247–1253.PubMedGoogle Scholar
  65. 65.
    Landschulz KT, Pathak RK, Rigotti A, Krieger M, Hobbs H. Regulation of scavenger receptor, class B, type I, a high density lipoprotein receptor, in liver and steroidogenic tissues of the rat. J Clin Invest 1996;98:984–995.PubMedGoogle Scholar
  66. 66.
    Quinn PG, Dombrausky LJ, Chen Y-DI, Payne AH. Serum lipoproteins increase testosterone production in hCG-desensitized Leydig cells. Endocrinology 1981;109:1790–1792.PubMedGoogle Scholar
  67. 67.
    Schumacher M, Schwarz M, Leidenberger F. Desensitization of mouse Leydig cells in vivo: evidence for the depletion of cellular cholesterol. Biol Reprod 1985;33:335–345.PubMedGoogle Scholar
  68. 68.
    Schreiber JR, Weinstein DB, Hsueh AJ. Lipoproteins stimulate androgen production by cultured rat testis cells. J Steroid Biochem 1982;16:39–43.PubMedGoogle Scholar
  69. 69.
    Klinefelter GR, Ewing LL. Optimizing testosterone production by purified adult rat Leydig cells in vitro. In Vitro Cell Dev Biol 1988;24:545–549.Google Scholar
  70. 70.
    Chen Y-DI, Kraemer FB, Reaven GM. Identification of specific high density lipoprotein-binding sites in rat testis and regulation of binding by human chorionic gonadotropin. J Biol Chem 1980;255:9162–9167.PubMedGoogle Scholar
  71. 71.
    Reaven E, Cortez Y, Leers-Sucheta S, Nomoto A, Azhar S. Dimerization of the scavenger receptor class B type I: formation, function, and localization in diverse cells and tissues. J Lipid Res 2004;45:513–528.PubMedGoogle Scholar
  72. 72.
    Benahmed M, Reventes J, Saez JM. Steroidogenesis of cultured purified pig Leydig cells: Effects of lipoproteins and human chorionic gonadotropin. Endocrinology 1983; 112:1952–1957.PubMedGoogle Scholar
  73. 73.
    Benahmed M, Dellamonica C, Haour F, Saez JM. Specific low density lipoprotein receptors in pig Leydig cells: Role of this lipoprotein in cultured Leydig cell steroidogenesis. Biochem Biophys Res Commun 1981;99:1123–1130.PubMedGoogle Scholar
  74. 74.
    Carr BR, Parker CR Jr., Ohashi M, MacDonald PC, Simpson ER. Regulation of human fetal testicular secretion of testosterone: Low-density lipoprotein-cholesterol and cholesterol synthesized de novo as steroid precursor. Am J Obstet Gynecol 1983; 146:241–247.PubMedGoogle Scholar
  75. 75.
    Wrobel KH, Sinowatz F, Mademann R. Intertubular topography in the bovine testis. Cell Tissue Res 1981;217:289–310.PubMedGoogle Scholar
  76. 76.
    Liao C, Reaven E, Azhar S. Age-related decline in the steroidogenic capacity of isolated rat Leydig cells: a defect in cholesterol mobilization and processing. J Steroid Biochem Mol Biol 1993;46:39–47.PubMedGoogle Scholar
  77. 77.
    Paniagua R, Amat P, Nistal M, Martin A. Ultrastructure of Leydig cells in human ageing testes. J Anat 1986;146:173–183.PubMedGoogle Scholar
  78. 78.
    Andreis PG, Cavallini L, Mazzocchi G, Meneghelli V, Nussdorfer GG. Lipid droplets in the secretory response of Leydig cells of normal and hCG-treated rats. J Submicrosc Cytol Pathol 1990;22:361–366.PubMedGoogle Scholar
  79. 79.
    Chung KW, Hamilton JB. Testicular lipids in mice with testicular feminization. Cell Tissue Res 1975;160:69–80.PubMedGoogle Scholar
  80. 80.
    Bergh A, Ason BA, Damber JE, Hammar M, Selstam, G. Steroid biosynthesis and Leydig cell morphology in adult unilaterally cryptorchid rats. Acta Endocrinol (Copenh) 1984;107:556–562.Google Scholar
  81. 81.
    Ezeasor DN. Light and electron microscopical observations on the Leydig cells of the scrotal and abdominal testes of naturally unilateral cryptorchid West Africa dwarf goats. J Anat 1985;141:27–40.PubMedGoogle Scholar
  82. 82.
    Damber JE, Bergh A, Janson PO. Leydig cell function and morphology in the rat testis after exposure to heat. Andrologia 1980;12:12–19.PubMedGoogle Scholar
  83. 83.
    Cao G, Zhao L, Stangel H, et al. Developmental and hormonal regulation of murine scavenger receptor, class B, type 1. Mol Endocrinol 1999;13:1460–1473.PubMedGoogle Scholar
  84. 84.
    Rao RM, Jo Y, Leers-Sucheta S, Bose HS, Miller WL, Azhar S, Stocco DM. Differential regulation of steroid hormone biosynthesis in R2C and MA-10 Leydig cells: Role of SR-BI-mediated selective cholesteryl ester transport. Biol Reprod 2003;68:114–121.PubMedGoogle Scholar
  85. 85.
    Freeman DA. Constitutive steroidogenesis does not require the actions of cAMP on cholesteryl ester hydrolysis or internalization of plasma membrane cholesterol. Endocr Res 1996;22:557–562.PubMedGoogle Scholar
  86. 86.
    Tong MH, Christenson LK, Song W-C. Aberrant cholesterol transport and impaired steroidogenesis in Leydig cells lacking estrogen sulfotransferase. Endocrinology 2004; 145:2487–2497.PubMedGoogle Scholar
  87. 87.
    Voelker DR. Organelle biogenesis and intracellular lipid transport in eukaryotes. Microbiol Rev 1991;55:543–560.PubMedGoogle Scholar
  88. 88.
    Prinz W. Cholesterol trafficking in the secretory and endocytic systems. Semin Cell Dev Biol 2002; 13:197–203.PubMedGoogle Scholar
  89. 89.
    Hall PF. The roles of microfilaments and intermediate filaments in the regulation of steroid synthesis. J Steroid Biochem Mol Biol 1995;55:601–605.PubMedGoogle Scholar
  90. 90.
    Feuilloley M, Vaudry H. Role of cytoskeleton in adrenocortical cells. Endocr Rev 1996;17:269–288.PubMedGoogle Scholar
  91. 91.
    Stocco DM, Clark BJ. Regulation of the acute production of steroids in steroidogenic cells. Endocr Rev 1996;17:221–244.PubMedGoogle Scholar
  92. 92.
    Gallegos AM, Atshaves BP, Storey SM, et al. Gene structure, intracellular localization, and functional roles of sterol carrier protein-2. Prog Lipid Res 2001;40:498–563.PubMedGoogle Scholar
  93. 93.
    Kamal A, Goldstein LS. Connecting vesicle transport to the cytoskeleton. Curr Opin Cell Biol 2000;12:503–508.PubMedGoogle Scholar
  94. 94.
    Alder NN, Theg SM. Energy use by biological protein transport pathways. Trends Biochem Sci 2003;28:442–451.PubMedGoogle Scholar
  95. 95.
    Styers ML, Kowalczyk AP, Faundez V. Intermediate filaments and vesicular membrane traffick: The odd couple’s first dance? Traffic 2005;6:359–365.PubMedGoogle Scholar
  96. 96.
    Pointing CP, Aravind L. START: a lipid-binding domain in StAR, HD-ZIP and signaling proteins. Trends Biochem Sci 1999;130–132.Google Scholar
  97. 97.
    Strauss JF III, Kishida T, Christenson LK, Fujimoto T, Hiroi H. START domain proteins and the intracellular trafficking of cholesterol in steroidogenic cells. Mol Cell Endocrinol 2003;202:59–65.PubMedGoogle Scholar
  98. 98.
    Soccio RE, Breslow JL. StAR-related lipid transfer (START) proteins: Mediators of intracellular lipid metabolism. J Biol Chem 2003;278:22,183–22,186.Google Scholar
  99. 99.
    Soccio RE, Adams RM, Maxwell KN, Breslow JL. Differential gene regulation of StarD4 and StarD5 cholesterol transfer proteins: Activation of StarD4 by sterol regulatory element-binding protein-2 and StarD5 by endoplasmic reticulum stress. J Biol Chem 2005;280:19,410–19,418.Google Scholar
  100. 100.
    Saltarelli D, De la Llosa-Hermier MP, Tertrin-Clary C, Hermier C. Effects of antimicro-tubular agents in cAMP production and in steroidogenic response of isolated rat Leydig cells. Biol Cell 1984;52:259–266.PubMedGoogle Scholar
  101. 101.
    Bilinska B. Visualization of the cytoskeleton in Leydig cells in vitro: effect of luteinizing hormone and cytoskeletal disrupting drugs. Histochemistry 1989;93:105–110.PubMedGoogle Scholar
  102. 102.
    Clark MA, Shay JW. The role of tubulin in the steroidogenic response of murine adrenal and rat Leydig cells. Endocrinology 1981;109:2261–2263.PubMedGoogle Scholar
  103. 103.
    Rainey WE, Kramer RE, Mason JI, Shay JW. The effects of taxol, a microtubule-stabilizing drug, on steroidogenic cells. J Cell Physiol 1985;123:17–24.PubMedGoogle Scholar
  104. 104.
    Temple R, Wolf J. Stimulation of steroid secretion by antimicrotubular agents. J Biol Chem 1973;248:2691–2698.PubMedGoogle Scholar
  105. 105.
    Hall PF, Charponnier C, Nakamura M, Gabbiani G. The role of microfilaments in the response of Leydig cells to Luteinizing hormone. J Steroid Biochem 1979;11:1361–1366.PubMedGoogle Scholar
  106. 106.
    Murono EK, Lin T, Osterman J, Nankin HR. The effects of cytochlasin B on testosterone synthesis by interstitial cells of rat testis. Biochim Biophys Acta 1980;633:228–236.PubMedGoogle Scholar
  107. 107.
    Hall PF, Charponnier C, Gabbiani G. Role of actin in response of Leydig cells to luteinizing hormone. In: Steinberger A, Steinberger E, eds. Testicular development structure and function. New York, NY: Raven Press, 1980;229–235.Google Scholar
  108. 108.
    Hall PF, Osawa S, Mrotek JJ. Influence of calmodulin on steroid synthesis in Leydig cells from rat testis. Endocrinology 1981;109:1677–1682.PubMedGoogle Scholar
  109. 109.
    Hall PF, Almahbobi G. Roles of microfilaments and intermediate filaments in adrenal steroidogenesis. Micros Res Tech 1997;36:463–479.Google Scholar
  110. 110.
    Russell LD, Amlani SR, Vogl AW, Weber JE. Characterization of filaments within Leydig cells of the rat testis. Am J Anat 1987;178:231–240.PubMedGoogle Scholar
  111. 111.
    Almahbobi G, Williams LJ, Han XG, Hall PF. Binding of lipid droplets and mitochondria to intermediate filaments in rat Leydig Cells. J Reprod Fertil 1993;98:209–217.PubMedGoogle Scholar
  112. 112.
    Vahouny GV, Chanderbhan R, Kharroubi A, Noland BJ, Pastuszyn A, Scallen TJ. Sterol carrier and lipid transfer proteins. Adv Lipid Res 1987;22:83–113.PubMedGoogle Scholar
  113. 113.
    Wirtz KWA. Phospholipid transfer proteins. Annu Rev Biochem 1991;60:73–99.PubMedGoogle Scholar
  114. 114.
    Chanderbhan R, Noland BJ, Scallen TJ, Vahouny GV. Sterol carrier protein2: Delivery of cholesterol from adrenal lipid droplets to mitochondria for pregnenolone synthesis. J Biol Chem 1982;257:8928–8934.PubMedGoogle Scholar
  115. 115.
    Chanderbhan R, Tanaka T, Strauss JF, et al. Evidence for sterol carrier protein2-like activity in hepatic, adrenal and ovarian cytosol. Biochem Biophys Res Comun 1983; 117:702–709.Google Scholar
  116. 116.
    van Noort M, Rommerts FFG, van Amerongen A, Wirtz KWA. Intracellular redistribution of SCP2 in Leydig cells after hormonal stimulation may contribute to increased pregnenolone production. Biochem Biophys Res Commun 1988;154:60–65.PubMedGoogle Scholar
  117. 117.
    Fuchs M, Hafer A, Münch C, et al. Disruption of the sterol carrier protein 2 gene in mice impairs biliary lipid and hepatic cholesterol metabolism. J Biol Chem 2001;276:48,058–48,065.Google Scholar
  118. 118.
    van Haren L, Teerds KJ, Ossendorp BC, et al. Sterol carrier protein 2 (non-specific lipid transfer protein) is localized in membranous fractions of Leydig cells and Sertoli cells but not in germ cells. Biochim Biophys Acta 1992;1124:288–296.PubMedGoogle Scholar
  119. 119.
    Mendis-Handagama SM, Watkins PA, Gelber SJ, Scallen TJ, Zirkin BR, Ewing LL. Luteinizing hormone causes rapid and transient changes in rat Leydig cell peroxisome volume and intraperoxisomal sterol carrier protein-2 content. Endocrinology 1990;127:2947–2954.PubMedGoogle Scholar
  120. 120.
    Mendis-Handagama SM, Watkins PA, Gelber SJ, Scallen TJ. The effect of chronic luteinizing hormone treatment on adult rat Leydig cells. Tissue Cell 1998;30:64–73.PubMedGoogle Scholar
  121. 121.
    Stocco DM, Teerds KJ, van Noort M, Rommerts FF. Effects of hypophysectomy and human chrionic gonadotropin on Leydig cell function in mature rats. J Endocrinol 1990; 126:367–375.PubMedGoogle Scholar
  122. 122.
    Mendis-Handagama SM, Watkins PA, Gelber SJ, Scallen TJ. Leydig cell peroxisomes and sterol carrier protein-2 in luteinizing hormone-deprived rats. Endocrinology 1992; 131:2839–2845.PubMedGoogle Scholar
  123. 123.
    Christenson LK, Strauss JF III. Steroidogenic acute regulatory protein (StAR) and the intramitochondrial translocation of cholesterol. Biochim Biophys Acta 2000;1529: 175–187.PubMedGoogle Scholar
  124. 124.
    Stocco DM. StAR protein and the regulation of steroid hormone biosynthesis. Annu Rev Physiol 2001;63:193–213.PubMedGoogle Scholar
  125. 125.
    Jefcoate C. High-flux mitochondrial cholesterol trafficking, a specialized function of the adrenal cortex. J Clin Invest 2002;110:881–890.PubMedGoogle Scholar
  126. 126.
    Manna PR, Stocco DM. Regulation of the steroidogenic acute regulatory protein expression: functional and physiological consequences. Curr Drug Targets Immune Endocr Metabol Disord 2005;5:93–108.PubMedGoogle Scholar
  127. 127.
    Papadopoulos V. Peripheral-type benzodiazepine/diazepam binding inhibitor receptor: biological role in steroidogenic cell function. Endocr Rev 1993;14:222–240.PubMedGoogle Scholar
  128. 128.
    Gavish M, Bachman I, Shoukrun R, Katz Y, Veenman L, Weisinger G, Weizman A. Enigma of the peripheral benzodiazepine receptor. Pharmacol Rev 1999;51:629–650.PubMedGoogle Scholar
  129. 129.
    Casellas P, Galiegue S, Basile AS. Peripheral benzodiazepine receptors and mitochondrial function. Neurochem Int 2002;40:475–486.PubMedGoogle Scholar
  130. 130.
    Lacapere JJ, Papadopoulos V Peripheral-type benzodiazepine receptor: structure and function of cholesterol-binding protein in steroid and bile acid biosynthesis. Steroids 2003; 68:569–585.PubMedGoogle Scholar

Copyright information

© Humana Press Inc., Totowa, NJ 2007

Authors and Affiliations

  • Salman Azhar
    • 1
    • 2
  • Eve Reaven
    • 1
  1. 1.Geriatric Research, Educationnn and Clinical Center (GRECC)VA Palo Alto Health Care SystemPalo Alto
  2. 2.Division of Gastroenterology and Hepatology, Department of MedicineStanford University School of MedicineStanford

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