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Regulation of the Rate-Determining Step in the Steroidogenic Cascade in Rat Leydig Cells

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Regulation of the Rate-Determining Step in the Steroidogenic Cascade in Rat Leydig Cells Regulation of the Rate-Determining Step in the Steroidogenic Cascade in Rat Leydig Cells Regulatie van de Snelheids-Bepalende Stap in de Steroldogene Cascade in Leydig Cellen van de Rat Proefschrift ter verkrijging van de graad van doctor aan de Erasmus Universiteit Rotterdam op gezag van de Rector Magnificus Prof. Dr P. W.C. Akkermans M.A. en volgens besluit van het College voor Promoties. De openbare verdediging zal plaatsvinden op woensdag 30 oktober 1996 om 11,45 uur door Elisabeth Jacqueline Maria van Haren geboren te Vught omslag: 'Mitochondrial Mall' door Katinka van Haren Promotie-commissie Promotor Prof. dr. J.A. Grootegoed Overige leden: Prof. dr. H.J. Degenhart Prof. dr. F.H. de Jong Prof. dr. A.G.H. Smals Co-promotor Dr. F.F.G. Rommerts :::I~NDOCRINOLOGY ROTlfROAIt Dit proefschrift werd bewerkt binnen de Vakgroep Endocrinologie & Voortpianting van de Faculteit der Geneeskunde en Gezondheidswetenschappen, Erasmus Universiteit Rotterdam. Contents Abbreviations and Trivial Names 7 Chapter 1 Introduction 9 1.1. Testicular steroid production 10 1.1.1. Leydig cells 10 1.1.2. The steroidogenic cascade 11 1.1.3. Rate-determining step in the steroidogenic cascade 16 1.1.4. Measurement of Leydig cell steroid production 18 1.2. Regulation of the steroidogenic cascade by LH 19 1.2.1. Short-tenn effects of LH 19 1.2.2. Long-tenn effects of LH 23 1.2.3. Modulation of LH action by local factors 24 1.3. Aim and scope of this thesis 26 Chapter 2 Sterol Carrier Protein (Non-Specific Lipid Transfer Protein) is Localized in Membranous Fractions of Leydig Cells and Sertoli Cells but not in Germ Cells 27 Chapter 3 Measurement of Steroidogenesis in Rodent Leydig Cells: a Comparison between Pregnenolone and Testosterone Production 45 Chapter 4 Luteinizing Hormone Induction of the Cholesterol Side-Chain Cleavage Enzyme in Cultured Immature Rat Leydig Cells: no Role of Insulin-like Growth Factor-I? 59 4 Chapter 5 Inhibition of the Luteinizing Hormoue-Dependent Indnction of Cholesterol Side-Chain Cleavage Enzyme in Innnature Rat Leydig Cells by Sertoli Cell Products 77 Chapter 6 General Discussion 91 6.1. Introduction 92 6.2. Measurement of CSCC enzyme activity 92 6.3. Short-term regulation by LH: any role for SCI',? 93 6.4. Clinical disorders associated with defects in the steroidogenic cascade 95 6.5. LH induction of the CSCC enzyme: no role for IGF-I? 97 6.6. Regulation of LH induction of CSCC enzyme by paracrine factors (other than IGF-I) 100 References 102 Samenvatting 119 Dankwoord 122 Curriculum vitae 124 5 6 Abbreviations and Trivial Names ACTH adrenocorticotropic homlOne AMH anti-mullerian honnone BSA bovine serum albumin cAMP cyclic adenosine 3' ,5'-monophosphate (c)DNA (complementary) deoxyribonucleic acid CSCC cholesterol side-chain cleavage DAG diacylglycerol dbcAMP dibutyryl adenosine cyclic-3' ,5' -monophosphate DB! diazepam-binding inhibitor EGF epidennal growth factor FSH follicle-stimulating honnone, or follitropin GH growth honnone GnRH gonadotropin-releasing hormone hCG human chorionic gonadotropin 3JlHSD 3B-hydroxysteroid dehydrogenase 17JlHSD 17Jl-hydroxysteroid dehydrogenase IGF insulin-like growth factor IGFBP insulin-like growth factor binding protein IP, inositol triphosphate kb kilo base kDa kilo Dalton LH luteinizing honnone, or lutropin LHRH luteinizing hormone-releasing hormone mRNA messenger ribonucleic acid nsL-TP non-specific lipid transfer protein P450c17 17a-hydroxylase cytochrome P450 P450arom aromatase cytochrome P450 P450scc cholesterol side-chain cleavage cytochrome P450 PBR peripheral benzodiazepine receptor SAP steroidogenesis activator polypeptide TGFJl transforming growth factor Jl TNPa tumour necrosis factor CI. SCCM Sertoli cell-conditioned medium SCP, sterol carrier protein 2 StAR steroidogenic acute regulatory protein VDAC voltage-dependent anion channel 7 8 Chapter 1 Introduction 9 1.1. Testicular steroid production The testis consists of two compartments: the seminiferous tubules and the interstitium. The primary function of the seminiferous tubules is the production of spermatozoa. The developing germ cells are embedded in Sertoli cells, which form the blood-testis barrier by specialized junctions in-between Sertoli cells (De Kretser and Kerr, 1988). The seminiferous tubules are surrounded by a basal lamina and peri tubular myoid cells. The interstitium contains Leydig cells (Leydig, 1850), blood vessels, lymphatics, and macrophages. The main function of the interstitial tissue is production of androgens by the Leydig cells. 1.1.1. Leydig cells Androgens, produced by the Leydig cells, are involved in initiation and maintenance of spermatogenesis (Clermont and Harvey, 1965), development of the internal and external genitalia, the secondary sexual characteristics, and the musculoskeletal system, and feedback inhibition in the gonadal-hypothalamo-pituitary axis. Androgen action is mediated by the androgen receptor, an intracellular protein that is activated upon hormone binding. The hormone-receptor complex can subsequently regulate the transcription of androgen responsive genes, which results in changes in cell function (Beato, 1989). Androgen action in androgen target cells is determined mainly by the presence of the androgen receptor, but also by the enzyme 5ar-reductase. This enzyme, responsible for the conversion of testosterone into 5ar-dihydrotestosterone, is present in most androgen target tissues. Both testosterone and 5ar-dillydrotestosterone can bind to the androgen receptor. 5ar­ Dihydrotestosterone is a more potent androgen (Grino et 01., 1990), and it binds with a higher affinity to the androgen receptor than testosterone (Veldscholte, 1993). Luteinizing hormone (LH), produced by the pituitary gland, is the main regulator of Leydig cell steroidogenesis (Bartke et 01., 1978; Hall, 1988). The production and release ofLH are under the control of luteinizing hormone-releasing hormone (LHRH, also known as gonadotropin-releasing hormone: GnRH), a decapeptide produced by the hypothalamus (Hodgson et 01., 1983; Fink, 1988). In response to LH, the plasma testosterone level increases and acts as a negative feedback signal to inhibit the release of both LHRH and LH (Cunningham and Huckins, 1979). Althougb LH is the main regulator of Leydig cell steroidogenesis, tbere is abundant evidence, both from ill vivo and ill vitro experiments, that the effect of LH can be modulated by other hormones and by local factors produced in the testis (see 1.2.3.). 10 1.1.2. The steroidogenic cascade For Leydig cell steroidogenesis, cholesterol is the obligate precursor. Cholesterol may be obtained from three different sources: 1) Lipoproteins - Leydig cells are able to take up cholesterol from plasma lipoproteins. Both MA-lO Leydig tumour cells (Freeman and Ascoli, 1983) and pig Leydig cells (Benahmed ef al., 1983) use low density lipoproteins, while rat Leydig cells preferentially use high density lipoproteins (Chen ef al., 1980). 2) Intracellular stores - In Leydig cells of various species, stores of esterified cholesterol are found in lipid droplets in the cytoplasm (Almahbobi ef al., 1993). However, compared to the steroidogenic adrenal cells or luteinized granulosa cells, lipid droplets in Leydig cells are far less prominent. Even though Leydig cells do not store large quantities of cholesteryl esters, they can utilize these esters. Upon hormone stimulation the stores are depleted (Christensen, 1975) and the cellular amount of free cholesterol is increased, through cAMP-dependent protein kinase activation of cytoplasmic cholesterol ester hydrolase (Trzeciak and Boyd, 1973; Pedersen ef al., 1980) and suppression of acyl-CoA:cholesterol acyItransferase (Mikami ef al., 1984). Cholesterol can also be stored as unesterified cholesterol in the plasma membrane. MA-l0 Leydig tumour cells preferentially use this nonesterified cholesterol as a substrate for steroid production (Freeman, 1987). 3) De IIOVO synthesis - Rat Leydig cells contain all the enzymes necessary for de IIOVO synthesis of cholesterol. Newly synthesized cholesterol is either used immediately for steroid production or stored in membrane systems. The morphological characteristics of Leydig cells are consistent with a large synthetic capacity to produce cholesterol, in that the endoplasmic reticulum is particularly prominent (Iehihara, 1970; Russo, 1971). Although different cholesterol sources can be important for Leydig cell steroidogenesis (Hall, 1994), rat Leydig cells preferentially use intracellularly produced cholesterol as substrate for androgen production (Charreau ef al., 1981; Van der Molen and Rommerts, 1981). Steroid production does not take place until cholesterol is transported to a pool where it is available for metabolism by the cholesterol side-chain cleavage (CSCC) enzyme. This steroidogenic pool is located in the inner mitochondrial membrane (Seybert ef al., 1979; Privalle ef al., 1987). Prior to the accumulation of cholesterol into this steroidogenic pool, cholesterol is transported to a pre-steroidogenic pool (Stevens ef al., 1993), which is located in the outer mitochondrial membrane (Frivalle ef al., 1983, 1987). The 11 extracellular Intracellular uptake from I Intracellular -;-___ de novo lipoproteins ---)!> stores ·E synthesis \ inlracellular cholesterol tralllcking/ \11 cholesterol In pre·steroldogenio pool hormonally 1 controlled ------...,)!> cholesterol In steroidogenic pool cholesterol side-chai,..1 cleavage process AbOPH pregnenolone isocaproaldehyde ! metabolism into various steroids Fig. 1. Supply oj cllO/estero/jor
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