The effects of different culture media, glucose, pyridine nucleotides and adenosine on the activity of 11β-hydroxysteroid dehydrogenase in rat Leydig cells

Ferguson, Stewart; Pallikaros, Zakos; Michael, A.E; Cooke, B. A.

doi:10.1016/s0303-7207(99)00186-0

Cited by 27 publications

(16 citation statements)

References 23 publications

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“…Our findings are consistent with recent studies reporting that lack of G6P availability to H6PDH is associated with impaired hepatic 11b-HSD1 reductase activity in hypoglycemic mice (Chou et al 2002). Moreover, CBX inhibition of hepatic 11b-HSD1 reductase activity itself decreased NADP regeneration from NADPH in ER by preventing the conversion of 11-dehydrocorticosterone to corticosterone, thereby impairing an effective pathway for supplying NADP as cofactor to H6PDH linked to the reduction of H6PDH activity (Ferguson et al 1999). These findings agree with the notion that H6PDH activity is dependent on luminal NADP availability, which can be regenerated by oxidizing luminal NADPH in a reaction catalyzed by 11b-HSD1 (Hino & Minakami 1982, Csala et al 2006).…”

Section: Discussionsupporting

confidence: 93%

Reduction of hepatic glucocorticoid receptor and hexose-6-phosphate dehydrogenase expression ameliorates diet-induced obesity and insulin resistance in mice

Liu

Nakagawa²,

Wang³

et al. 2008

Journal of Molecular Endocrinology

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Intracellular glucocorticoid (GC) receptor (GR) function determines tissue sensitivity to GCs and strongly affects the development of type 2 diabetes and obesity. 11b-hydroxysteroid dehydrogenase type 1 (11b-HSD1) mediates intracellular steroid exposure to mouse liver GR by prereceptor reactivation of GCs and is crucially dependent on hexose-6-phosphate dehydrogenase (H6PDH)-generating NADPH system. Pharmacological inhibition of 11b-HSD1 improves insulin intolerance and obesity. Here, we evaluated the potential beneficial effects of 11b-HSD1 inhibitor carbenoxolone (CBX) in diet-induced obese (DIO) and insulin-resistant mice by examining the possible influence of CBX on the expression of GR, 11b-HSD1, and H6PDH in vivo and in vitro in hepatocytes. Treatment of DIO mice with CBX markedly reduced hepatic GR mRNA levels and reduced weight gain, hyperglycemia, and insulin resistance. The reduction of hepatic GR gene expression was accompanied by CBX-induced inhibition of both 11b-HSD1 and H6PDH activity and mRNA in the liver. Moreover, CBX treatment also suppressed the expression of both phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase enzyme (G6Pase) mRNA and improved hepatic [1,[2][3] H] deoxy-D-glucose uptake in DIO mice. In addition, the treatment of primary cultures of hepatocytes with increasing concentrations of CBX led to a dose-dependent downregulation of GR mRNA levels, which correlated with the suppression of both 11b-HSD1 and H6PDH activity and their gene expression. Addition of CBX to primary hepatocytes also resulted in suppression of both PEPCK and G6Pase mRNA levels. These findings suggest that CBX exerts some of its beneficial effects, at least in part, by inhibiting hepatic GR and H6PDH expression.

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Section: Discussionsupporting

confidence: 93%

Reduction of hepatic glucocorticoid receptor and hexose-6-phosphate dehydrogenase expression ameliorates diet-induced obesity and insulin resistance in mice

Liu

Nakagawa²,

Wang³

et al. 2008

Journal of Molecular Endocrinology

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“…We subsequently confirmed that in the MA10 mouse tumour Leydig cell line, the direction of the reaction for 11bHSD1 was determined by the concentrations of respiratory substrates (e.g. glucose) in the medium (Ferguson et al 1999).…”

Section: Trends In Nadp(h)-and Nadsupporting

confidence: 66%

11β-Hydroxysteroid dehydrogenase expression and activities in bovine granulosa cells and corpora lutea implicate corticosteroids in bovine ovarian physiology

Thurston

Abayasekara

Michael

2007

Journal of Endocrinology

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Cortisol-cortisone metabolism is catalysed by the bi-directional NADP(H)-dependent type 1 11b-hydroxysteroid dehydrogenase (11bHSD1) enzyme and the oxidative NAD C -dependent type 2 11bHSD (11bHSD2). This study related the expression of 11bHSD1 and 11bHSD2 enzymes (mRNA and protein) to net 11-ketosteroid reductase and 11b-dehydrogenase (11b-DH) activities in bovine follicular granulosa and luteal cells. Granulosa cells were isolated from follicles of !4, 4-8, O8 and O12 mm in diameter in either the follicular or luteal phase of the ovarian cycle. Luteal cells were obtained from corpora lutea (CL) in the early non-pregnant luteal phase. Enzyme expression was assessed by reverse transcription-PCR and western blotting, while enzyme activities were measured over 1 h in cell homogenates using radiometric conversion assays with 100 nM [ 3 H]cortisone or [ 3 H]cortisol and pyridine dinucleotide cofactors. Irrespective of follicle diameter, the expression of 11bHSD2 and NAD C -dependent oxidation of cortisol predominated in granulosa cells harvested in the follicular phase. In contrast, in granulosa cells obtained from luteal phase follicles and in bovine luteal cells, expression of 11bHSD1 exceeded that of 11bHSD2 and the major enzyme activity was NADP C -dependent cortisol oxidation. Increasing follicular diameter was associated with progressive increases in expression and activities of 11bHSD2 and 11bHSD1 in follicular and luteal phase granulosa cells respectively. In follicular phase granulosa cells from antral follicles !12 mm, 11bHSD1 migrated with a molecular mass of 34 kDa, whereas in the dominant follicle, CL and all luteal phase granulosa cells, a second protein band of 68 kDa was consistently detected. In all samples, 11bHSD2 had a molecular mass of 48 kDa, but in large antral follicles (O8 mm), there was an additional immunoreactive band at 50 kDa. We conclude that 11bHSD2 is the predominant functional 11bHSD enzyme expressed in follicular phase granulosa cells from growing bovine antral follicles. In contrast, in bovine granulosa cells from dominant or luteal phase follicles, and in bovine luteal cells from early non-pregnant CL, 11bHSD1 is the major glucocorticoid-metabolising enzyme. The increasing levels of cortisol inactivation by the combined NADP C -and NAD C -dependent 11b-DH activities suggest a need to restrict cortisol access to corticosteroid receptors in the final stages of follicle development.

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“…However, in hepatoma and adipocyte cell lines which express endogenous H6PDH, 11␤-reductase activity predominates irrespective of extracellular glucose levels (177). Conversely, rat Leydig cells, which express ample H6PDH (241), switch 11␤-HSD1 activity from reductase to dehydrogenase when glucose concentrations fall (196). The extent to which this happens in vivo is unclear.…”

Section: H6pdh Determines 11␤-hsd1 Reaction Directionmentioning

confidence: 99%

11β-Hydroxysteroid Dehydrogenases: Intracellular Gate-Keepers of Tissue Glucocorticoid Action

Chapman

Holmes

Seckl

2013

Physiological Reviews

713

601

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Glucocorticoid action on target tissues is determined by the density of “nuclear” receptors and intracellular metabolism by the two isozymes of 11β-hydroxysteroid dehydrogenase (11β-HSD) which catalyze interconversion of active cortisol and corticosterone with inert cortisone and 11-dehydrocorticosterone. 11β-HSD type 1, a predominant reductase in most intact cells, catalyzes the regeneration of active glucocorticoids, thus amplifying cellular action. 11β-HSD1 is widely expressed in liver, adipose tissue, muscle, pancreatic islets, adult brain, inflammatory cells, and gonads. 11β-HSD1 is selectively elevated in adipose tissue in obesity where it contributes to metabolic complications. Similarly, 11β-HSD1 is elevated in the ageing brain where it exacerbates glucocorticoid-associated cognitive decline. Deficiency or selective inhibition of 11β-HSD1 improves multiple metabolic syndrome parameters in rodent models and human clinical trials and similarly improves cognitive function with ageing. The efficacy of inhibitors in human therapy remains unclear. 11β-HSD2 is a high-affinity dehydrogenase that inactivates glucocorticoids. In the distal nephron, 11β-HSD2 ensures that only aldosterone is an agonist at mineralocorticoid receptors (MR). 11β-HSD2 inhibition or genetic deficiency causes apparent mineralocorticoid excess and hypertension due to inappropriate glucocorticoid activation of renal MR. The placenta and fetus also highly express 11β-HSD2 which, by inactivating glucocorticoids, prevents premature maturation of fetal tissues and consequent developmental “programming.” The role of 11β-HSD2 as a marker of programming is being explored. The 11β-HSDs thus illuminate the emerging biology of intracrine control, afford important insights into human pathogenesis, and offer new tissue-restricted therapeutic avenues.

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The effects of different culture media, glucose, pyridine nucleotides and adenosine on the activity of 11β-hydroxysteroid dehydrogenase in rat Leydig cells

Cited by 27 publications

References 23 publications

Reduction of hepatic glucocorticoid receptor and hexose-6-phosphate dehydrogenase expression ameliorates diet-induced obesity and insulin resistance in mice

Reduction of hepatic glucocorticoid receptor and hexose-6-phosphate dehydrogenase expression ameliorates diet-induced obesity and insulin resistance in mice

11β-Hydroxysteroid dehydrogenase expression and activities in bovine granulosa cells and corpora lutea implicate corticosteroids in bovine ovarian physiology

11β-Hydroxysteroid Dehydrogenases: Intracellular Gate-Keepers of Tissue Glucocorticoid Action

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