Multiple Mechanisms for Regulation of 3β-Hydroxysteroid Dehydrogenase/Δ5→Δ4-Isomerase, 17α-Hydroxylase/C17–20Lyase Cytochrome P450, and Cholesterol Side-Chain Cleavage Cytochrome P450 Messenger Ribonucleic Acid Levels in Primary Cultures of Mouse Leydig Cells*

Payne, Anita H.; Sha, Linli

doi:10.1210/endo-129-3-1429

Cited by 134 publications

(91 citation statements)

References 13 publications

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“…The Leydig cell responds to glucocorticoids. Glucocorticoids have been found to directly inhibit the transcription of genes encoding testosterone biosynthetic enzymes such as cytochrome P450-dependent cholesterol side chain cleavage enzyme, and cytochrome P450-dependent 17α-hydroxylase/C 17 -C 20 lyase [16,22]. Cholesterol transporting protein steroidogenic acute regulatory protein (StAR) gene is also repressed by glucocorticoids [23].…”

Section: Stress and Leydig Cell Functionmentioning

confidence: 99%

Rapid mechanisms of glucocorticoid signaling in the Leydig cell☆

Lian

Lin

et al. 2008

Steroids

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Stress-mediated elevations in circulating glucocorticoid levels lead to corresponding rapid declines in testosterone production by Leydig cells in the testis. In previous studies we have established that glucocorticoids act on Leydig cells directly, through the classic glucocorticoid receptor (GR), and that access to the GR is controlled prior to the GR by a metabolizing pathway mediated by the type 1 isoform of 11β-hydroxysteroid dehydrogenase (11βHSD1). This enzyme is bidirectional (with both oxidase and reductase activities) and in the rat testis is exclusively localized in Leydig cells where it is abundantly expressed and may catalyze the oxidative inactivation of glucocorticoids. The predominant reductase direction of 11βHSD1 activity in liver cells is determined by an enzyme, hexose-6-phosphate dehydrogenase (H6PDH), on the luminal side of the smooth endoplasmic reticulum (SER). Generation of the pyridine nucleotide cofactor NADPH by H6PDH stimulates the reductase direction of 11βHSD1 resulting in increased levels of active glucocorticoids in liver cells. Unlike liver cells, steroidogenic enzymes including 17β-hydroxysteroid dehydrogenase 3 (17βHSD3) forms the coupling with 11βHSD1. Thus the physiological concentrations of androstenedione serve as a substrate for 17βHSD3 utilizing NADPH to generate NADP+, which drives 11βHSD1 in Leydig cells primarily as an oxidase; thus eliminating the adverse effects of glucocorticoids on testosterone production. At the same time 11βHSD1 generates NADPH which promotes testosterone biosynthesis by stimulating 17βHSD3 in a cooperative cycle. This enzymatic coupling constitutes a rapid mechanism for modulating glucocorticoid control of testosterone biosynthesis. Under stress conditions, glucocorticoids also have rapid actions to suppress cAMP formation thus to lower testosterone production.

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Section: Stress and Leydig Cell Functionmentioning

confidence: 99%

Rapid mechanisms of glucocorticoid signaling in the Leydig cell☆

Lian

Lin

et al. 2008

Steroids

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“…Although the molecular mechanisms by which Gc decrease steroidogenesis have not been entirely defined, numerous studies have shown that Gc can inhibit expression of enzymes involved in testosterone biosynthesis such as Star, Cyp11a1, Cyp17a1, Hsd3b and Hsd17b3 (Hales & Payne 1989, Payne & Sha 1991, Wang et al 2000, Huang & Shirley 2001, Schwarzenbach et al 2003, Badrinarayanan et al 2006, Fon & Li 2007. Interestingly, variations in serum Gc content have no significant effect on circulating levels of LH and on its binding properties to its receptor, indicating that Gc repressive effects on Leydig cell steroidogenic capacity are not mediated by an indirect effect on pituitary LH production (Orr & Mann 1990, Orr et al 1994, Gao et al 1996.…”

Section: Introductionmentioning

confidence: 99%

Glucocorticoids antagonize cAMP-induced Star transcription in Leydig cells through the orphan nuclear receptor NR4A1

Martin¹,

Tremblay

2008

Journal of Molecular Endocrinology

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It is well established that stress, either physical or psychosocial, causes a decrease in testosterone production by Leydig cells. Glucocorticoids (Gc) are the main mediators of stress response and they convey their repressive effect on Leydig cells through the glucocorticoid receptor (GR). So far, various mechanisms have been proposed to explain the mechanism of action of Gc on Leydig cell steroidogenesis including repression of genes involved in testosterone biosynthesis. Several steroidogenic genes, including steroidogenic acute regulatory (STAR) protein, have been shown to be repressed by Gc in a GR-dependent manner but the underlying mechanisms remain to be fully elucidated. Here, we found that dexamethasone (Dex), a potent synthetic Gc, partly antagonizes the cAMP-dependent stimulation of the mouse Star promoter in MA-10 Leydig cells as revealed by transient transfection assays. This repression requires an element located at K95 bp previously implicated in the activation of the Star promoter by the nuclear receptors, NR4A1 and NR5A1. Dex was found to inhibit NR4A1-dependent transactivation of the Star promoter in Leydig cells by decreasing NR4A1, but not NR5A1, recruitment to the proximal Star promoter as determined by chromatin immunoprecipitation assay. Western blots revealed that Dex did not affect NR4A1 or NR5A1 expression in response to cAMP. These data suggest that NR4A1 would be associated with the GR in a transcriptionally inactive complex as previously demonstrated in pituitary corticotrope cells. Thus, our data provide new molecular insights into the stress-mediated suppression of testosterone production in testicular Leydig cells.

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“…The intra-testicular mechanism by which digoxin modulates steroidogenesis has not been well-de®ned, but a number of in vitro studies have shown that many compounds (e.g. lead or aminoglutethimide) may directly or indirectly target the enzymes required for the biosynthesis of testosterone in Leydig cells, including cytochrome P450 scc , P450 c 17, 3b-HSD, and 17-KSR (Payne & Sha, 1991;Thoreux et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

Inhibitory effect of digoxin on testosterone secretion through mechanisms involving decreases of cyclic AMP production and cytochrome P450_scc activity in rat testicular interstitial cells

H¹,

Wang

Tsai³

et al. 1998

British J Pharmacology

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1 In vivo and in vitro experiments were performed to examine inhibitory e ects of digoxin on testosterone secretion and to determine possible underlying mechanisms. 2 A single intravenous injection of digoxin (1 mg kg 71 ) decreased the basal and human chorionic gonadotropin (hCG)-stimulated plasma testosterone concentrations in adult male rats. 3 Digoxin (10 77 ± 10 74 M) decreased the basal and hCG-stimulated release of testosterone from rat testicular interstitial cells in vitro. 4 Digoxin (10 77 ± 10 74 M) also diminished the basal and hCG-stimulated production of cyclic 3' : 5'-adenosine monophosphate (AMP) and attenuated the stimulatory e ects of forskolin and 8-Br-cyclic AMP on testosterone production by rat testicular interstitial cells. 5 Digoxin (10 74 M) inhibited cytochrome P450 side chain cleavage enzyme (cytochrome P450 scc ) activity (conversion of 25-hydroxy cholesterol to pregnenolone) in the testicular interstitial cells but did not in¯uence the activity of other steroidogenic enzymes. 6 These results suggest that digoxin inhibits the production of testosterone in rat testicular interstitial cells, at least in part, via attenuation of the activities of adenylyl cyclase and cytochrome P450 scc .

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Multiple Mechanisms for Regulation of 3β-Hydroxysteroid Dehydrogenase/Δ⁵→Δ⁴-Isomerase, 17α-Hydroxylase/C_17–20Lyase Cytochrome P450, and Cholesterol Side-Chain Cleavage Cytochrome P450 Messenger Ribonucleic Acid Levels in Primary Cultures of Mouse Leydig Cells^*

Cited by 134 publications

References 13 publications

Rapid mechanisms of glucocorticoid signaling in the Leydig cell☆

Rapid mechanisms of glucocorticoid signaling in the Leydig cell☆

Glucocorticoids antagonize cAMP-induced Star transcription in Leydig cells through the orphan nuclear receptor NR4A1

Inhibitory effect of digoxin on testosterone secretion through mechanisms involving decreases of cyclic AMP production and cytochrome P450_scc activity in rat testicular interstitial cells

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Multiple Mechanisms for Regulation of 3β-Hydroxysteroid Dehydrogenase/Δ5→Δ4-Isomerase, 17α-Hydroxylase/C17–20Lyase Cytochrome P450, and Cholesterol Side-Chain Cleavage Cytochrome P450 Messenger Ribonucleic Acid Levels in Primary Cultures of Mouse Leydig Cells*

Cited by 134 publications

References 13 publications

Rapid mechanisms of glucocorticoid signaling in the Leydig cell☆

Rapid mechanisms of glucocorticoid signaling in the Leydig cell☆

Glucocorticoids antagonize cAMP-induced Star transcription in Leydig cells through the orphan nuclear receptor NR4A1

Inhibitory effect of digoxin on testosterone secretion through mechanisms involving decreases of cyclic AMP production and cytochrome P450scc activity in rat testicular interstitial cells

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Product

Resources

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Multiple Mechanisms for Regulation of 3β-Hydroxysteroid Dehydrogenase/Δ⁵→Δ⁴-Isomerase, 17α-Hydroxylase/C_17–20Lyase Cytochrome P450, and Cholesterol Side-Chain Cleavage Cytochrome P450 Messenger Ribonucleic Acid Levels in Primary Cultures of Mouse Leydig Cells^*

Inhibitory effect of digoxin on testosterone secretion through mechanisms involving decreases of cyclic AMP production and cytochrome P450_scc activity in rat testicular interstitial cells