Rat liver 11 beta-hydroxysteroid dehydrogenase complementary deoxyribonucleic acid encodes oxoreductase activity in a mineralocorticoid-responsive toad bladder cell line.

Duperrex, H.; Kenouch, S; Gaeggeler, H. P.; Seckl, Jonathan R.; Edwards, C. R. W.; Farman, Nicolette; Rossier, Bernard C.

doi:10.1210/endo.132.2.8425481

Cited by 43 publications

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“…These results conform with most previous studies of 11 -HSD-1 in intact cells (Duperrex et al 1993, Low et al 1994, Hundertmark et al 1995, Jamieson et al 1995, Rajan et al 1996, and more recently, with the predominant reaction direction in whole organs and in vivo (Kotelevtsev et al 1997). However, Monder et al (1994a) found significant 11 -dehydrogenation in rat Leydig cells, although reductase activity was not determined.…”

Section: Discussionsupporting

confidence: 91%

“…11 -Reductase predominance is seen in most transfected cells (Duperrex et al 1993, Low et al 1994 and in primary cultures of rat hepatocytes ( Jamieson et al 1995), lung cells (Hundertmark et al 1995), neurons (Rajan et al 1996), vascular smooth muscle cells (Brem et al 1995) and human adipose cells (Bujalska et al 1997). Moreover, 11 -HSD-1 reductase appears functionally important, since it amplifies glucocorticoid action via glucocorticoid receptors (GR) in transfected cells (Low et al 1994) and primary cultures (Hundertmark et al 1995, Rajan et al 1996.…”

Section: Introductionmentioning

confidence: 99%

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

Leckie

Welberg²,

Seckl³

1998

Journal of Endocrinology

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Abstract11 -Hydroxysteroid dehydrogenases (11 -HSDs) interconvert active corticosterone and inert 11-dehydrocorticosterone. In tissue homogenates, 11 -HSD type 1 (11 -HSD-1) exhibits both 11 -dehydrogenase (corticosterone inactivating) and 11 -reductase (corticosterone regenerating) activities, whereas 11 -HSD type 2 (11 -HSD-2) is an exclusive dehydrogenase. In the rat testis, 11 -HSD has been proposed to reduce glucocorticoid inhibition of testosterone production, promoting puberty and fertility. This hypothesis presupposes dehydrogenation predominates. 11 -HSD-1 immunoreactivity has been localised to Leydig cells. However, recent studies suggest that 11 -HSD-1 is predominantly an 11 -reductase in many intact cells. We therefore examined the expression and reaction direction of 11 -HSD isozymes in cultures of intact rat Leydig cells.Reverse transcriptase PCR demonstrated expression of 11 -HSD-1, but not 11 -HSD-2 mRNA in rat testis. Primary cultures of intact rat Leydig cells showed predominant 11 -reductase activity, activating 50-70% of 11-dehydrocorticosterone to corticosterone over 3 h, whereas 11 -dehydrogenation was <5%. Although both dexamethasone (10 nM) and corticosterone (1 µM) modestly inhibited LH-stimulated testosterone production by Leydig cells, inert 11-dehydrocorticosterone (1 µM) had similar effects, suggesting 11 -reductase is functionally important. Carbenoxolone (10 5 M) inhibited 11 -reduction in intact Leydig cells. However, although carbenoxolone reduced Leydig cell testosterone production, this also occurred in the absence of glucocorticoids, suggesting effects distinct from modulation of corticosteroid access to Leydig cells.In conclusion, rat Leydig cell 11 -HSD-1 is unlikely to reduce glucocorticoid access to testicular receptors. More likely, 11 -reductase amplifies glucocorticoid action, perhaps to maintain Leydig cell metabolic and endocrine functions.

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Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

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

Leckie

Welberg²,

Seckl³

1998

Journal of Endocrinology

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“…Some suggested it might be a lower affinity 11␤-dehydrogenase. However, studies in clonal amphibian and mammalian cells transfected with rat 11␤-HSD1 cDNA showed that, whilst bidirectional in homogenates, surprisingly it acts as a predominant 11␤-reductase in most intact cells and thus functionally amplifies glucocorticoid action (174,420). Indeed, in cells expressing 11␤-HSD1, cortisone (or 11dehydrocorticosterone) is equipotent with or even more potent than cortisol (or corticosterone) (206,231,646).…”

Section: ) (Figure 2)mentioning

confidence: 99%

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

Chapman

Holmes

Seckl

2013

Physiological Reviews

707

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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“…It is widely distributed, with high expression in several organs including the liver. Although 11 -HSD-1 shows bi-directional activity in tissue homogenates and purified microsomal fractions in vitro (Lakshmi & Monder 1988), near exclusive 11 -reduction has been demonstrated in both intact cells transfected with 11 -HSD-1 cDNA (Duperrex et al 1993) and primary cells in culture, including hepatocytes ( Jamieson et al 1995).…”

Section: Introductionmentioning

confidence: 99%

Interactions between oestradiol and glucocorticoid regulatory effects on liver-specific glucocorticoid-inducible genes: possible evidence for a role of hepatic 11beta-hydroxysteroid dehydrogenase type 1

Jamieson¹,

Nyirenda²,

Walker³

et al. 1999

Journal of Endocrinology

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In vitro, 11 -hydroxysteroid dehydrogenase type 1 (11 -HSD-1) catalyses the interconversion of active corticosterone and inert 11-dehydrocorticosterone. 11 -HSD-1 is highly expressed in liver, where the reaction direction is 11 -reduction, thus potentially increasing intrahepatic active glucocorticoid levels. Inhibition of 11 -HSD-1 increases insulin sensitivity in humans in vivo suggesting that hepatic 11 -HSD-1 plays a role in the maintenance or control of key glucocorticoid-regulated metabolic functions.We have selectively repressed hepatic 11 -HSD-1 in rats by oestradiol administration for 42 days. This nearly completely repressed hepatic 11 -HSD-1 mRNA expression and enzyme activity and reduced expression of hepatic glucocorticoid-inducible genes including phosphoenolpyruvate carboxykinase (PEPCK), the ratelimiting step in gluconeogenesis. Similar effects were seen after 3 weeks of oestradiol treatment. To examine whether this was due to any direct effect of oestradiol upon PEPCK, the experiment was repeated in adrenalectomised rats glucocorticoid replacement. In adrenalectomised rats, oestradiol did not attenuate hepatic PEPCK, whilst glucocorticoid replacement restored this action. Oestradiol did not alter hepatic metabolism of corticosterone by pathways other than 11 -HSD-1.These data suggest 11 -HSD-1 plays an important role in maintaining expression of key glucocorticoid-regulated hepatic transcripts. Enzyme inhibition may provide a useful therapeutic target for manipulating glucose homeostasis.

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Rat liver 11 beta-hydroxysteroid dehydrogenase complementary deoxyribonucleic acid encodes oxoreductase activity in a mineralocorticoid-responsive toad bladder cell line.

Cited by 43 publications

References 0 publications

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

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

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

Interactions between oestradiol and glucocorticoid regulatory effects on liver-specific glucocorticoid-inducible genes: possible evidence for a role of hepatic 11beta-hydroxysteroid dehydrogenase type 1

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