11beta-hydroxysteroid dehydrogenase is a predominant reductase in intact rat Leydig cells

Leckie, C; Welberg, Leonie; Seckl, Jonathan R.

doi:10.1677/joe.0.1590233

Cited by 59 publications

(31 citation statements)

References 40 publications

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“…In other tissues, 11 -dehydrogenase activity has been reported in intact cell preparations with the direction of 11 -HSD1 catalysis appearing to vary according to physiological or developmental status of a particular cell type. In Leydig and neuronal cells, as well as in human bone, both 11 -dehydrogenase and oxo-reductase activities have been observed (Ge et al 1997, Leckie et al 1998, Jellinck et al 1999, Cooper et al 2000. Only oxo-reductase activity has been detected in kidney cells of monkey origin (Cos-7) transiently transfected with rat 11 -HSD1 cDNA (Low et al 1994).…”

Section: Discussionmentioning

confidence: 99%

Hexose-6-phosphate dehydrogenase confers oxo-reductase activity upon 11β-hydroxysteroid dehydrogenase type 1

Bujalska¹,

Draper²,

Michailidou³

et al. 2005

Journal of Molecular Endocrinology

149

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Two isozymes of 11 -hydroxysteroid dehydrogenase (11 -HSD) interconvert active cortisol and inactive cortisone. 11 -HSD2 (renal) acts only as a dehydrogenase, converting cortisol to cortisone. 11 -HSD1 (liver) is a bi-directional enzyme in cell homogenates, whereas in intact cells it typically displays oxo-reductase activity, generating cortisol from cortisone. We recently established that cortisone reductase deficiency is a digenic disease requiring mutations in both the gene encoding 11 -HSD1 and in the gene for a novel enzyme located within the lumen of the endoplasmic reticulum (ER), hexose-6-phosphate dehydrogenase (H6PDH). This latter enzyme generates NADPH, the co-factor required for oxo-reductase activity. Therefore, we hypothesized that H6PDH expression may be an important determinant of 11 -HSD1 oxo-reductase activity. Transient transfection of chinese hamster ovary (CHO) cells with 11 -HSD1 resulted in the appearance of both oxo-reductase and dehydrogenase activities in intact cells. Co-transfection of 11 -HSD1 with H6PDH increased oxo-reductase activity whilst virtually eliminating dehydrogenase activity. In contrast, H6PDH had no effect on reaction direction of 11 -HSD2, nor did the cytosolic enzyme, glucose-6-phosphate dehydrogenase (G6PD) affect 11 -HSD1 oxo-reductase activity. Conversely in HEK 293 cells stably transfected with 11 -HSD1 cDNA, transfection of an H6PDH siRNA reduced 11 -HSD1 oxo-reductase activity whilst simultaneously increasing 11 -HSD1 dehydrogenase activity. In human omental preadipocytes obtained from 15 females of variable body mass index (BMI), H6PDH mRNA levels positively correlated with 11 -HSD1 oxo-reductase activity, independent of 11 -HSD1 mRNA levels. H6PDH expression increased 5·3-fold across adipocyte differentiation (P,0·05) and was associated with a switch from 11 -HSD1 dehydrogenase to oxo-reductase activity. In conclusion, H6PDH is a crucial determinant of 11 -HSD1 oxo-reductase activity in intact cells. Through its interaction with 11 -HSD1, H6PDH may represent a novel target in the pathogenesis and treatment of obesity.

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Section: Discussionmentioning

confidence: 99%

Hexose-6-phosphate dehydrogenase confers oxo-reductase activity upon 11β-hydroxysteroid dehydrogenase type 1

Bujalska¹,

Draper²,

Michailidou³

et al. 2005

Journal of Molecular Endocrinology

149

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“…This applies in primary cultures of cells from liver (Jamieson et al 1995), adipose tissue (Bujalska et al 1997), lung (Hundertmark et al 1995, hippocampus (Rajan et al 1996), and vascular smooth muscle (Brem et al 1995). In a few studies, for example in Leydig cells, 11 -dehydrogenase activity has been reported in apparently intact cell preparations (Phillips et al 1989), but others have found predominant 11 -reduction (Leckie et al 1998) and argued that Figure 2 The enzymatic reactions of 11 -HSD1. 11 -HSD1 activity levels can be determined by the urinary ratio THF+alloTHF:THE.…”

Section: Set-point Of 11 -Hsd1 Activitymentioning

confidence: 99%

11β-Hydroxysteroid dehydrogenase and the pre-receptor regulation of corticosteroid hormone action

Draper¹,

Stewart²

2005

Journal of Endocrinology

346

294

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“…Discrepancies in the literature on the relative predominance oxidation and reduction may have arisen from the use of incubation periods longer than ten minutes, given that linearity of the reaction velocities in assays of intact Leydig cells, necessary for accurate estimation of enzyme kinetic parameters, is lost after ten minutes. Culture of Leydig cells for several days prior to measurement of enzyme activity results in sharp declines in 11βHSD1 oxidative activity and predominance of the reductase [53]. This is not surprising because the two activities are inversely regulated: in rat Leydig cells, protein kinase C increases 11βHSD1 oxidation and inhibits reduction [54].…”

Section: A Rapid Action Of Glucocorticoids Via 11βhsd1mentioning

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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11beta-hydroxysteroid dehydrogenase is a predominant reductase in intact rat Leydig cells

Cited by 59 publications

References 40 publications

Hexose-6-phosphate dehydrogenase confers oxo-reductase activity upon 11β-hydroxysteroid dehydrogenase type 1

Hexose-6-phosphate dehydrogenase confers oxo-reductase activity upon 11β-hydroxysteroid dehydrogenase type 1

11β-Hydroxysteroid dehydrogenase and the pre-receptor regulation of corticosteroid hormone action

Rapid mechanisms of glucocorticoid signaling in the Leydig cell☆

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