Clinical implications of glucocorticoid metabolism by 11beta-hydroxysteroid dehydrogenases in target tissues

Quinkler, Marcus; Oelkers, W.; Diederich, Sven

doi:10.1530/eje.0.1440087

Cited by 47 publications

(29 citation statements)

References 128 publications

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“…A second PPAR-␥Ϫmodulated pathway that has been shown to be responsible for adipose tissue homeostasis involves the enzyme 11␤-HSD-1 (23), which locally converts inactive corticosteroids into potent glucocorticoid receptor agonists (41,42). Here we found that PPAR-␥ agonist treatment caused 11␤-HSD-1 expression to be greatly diminished in VF, but not in SF.…”

Section: Discussionmentioning

confidence: 65%

PPAR-γ Activation Mediates Adipose Depot−Specific Effects on Gene Expression and Lipoprotein Lipase Activity

et al. 2003

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This study sought to determine whether the adipose depot؊specific (subcutaneous [SF] vs. visceral [VF])action of peroxisome proliferator؊activated receptor-␥ (PPAR-␥) agonists on fat deposition extends to the expression of lipoprotein lipase (LPL) and other key adipose lipid metabolism genes, and whether changes in LPL impact triglyceridemia. Rats were fed a standard diet or an obesity-promoting diet for 3 weeks, with or without treatment with COOH, a nonthiazolidinedione PPAR-␥ agonist. Treatment effects were essentially similar in both dietary cohorts. COOH did not affect weight gain, but increased SF (inguinal) fat mass twofold and reduced VF (retroperitoneal) accretion by half. Corresponding depot-specific alterations were observed in mRNA levels of the glucocorticoid-activating enzyme 11␤-hydroxysteroid dehydrogenase 1 (11␤-HSD-1) and the thermogenic modulator uncoupling protein 1 (UCP-1). COOH increased brown adipose tissue (BAT) weight and LPL availability by five-to eightfold. In rats refed standard diet after a 24-h fast, COOH reduced the insulin excursion by half. The agonist increased SF LPL activity and mRNA levels, but had no effect on VF LPL. The two-to threefold postprandial increase in plasma triglycerides (TGs) was abrogated in COOH-treated rats, likely in part because of increased LPL in SF and BAT. Thus PPAR-␥ agonist treatment had a powerful, site-specific effect on adipose metabolism and lipid deposition, and greatly impacted the postprandial handling of TG-rich lipoproteins. These depot-specific effects may be mediated by differential regulation of key metabolic genes, including LPL, 11␤-HSD-1, and UCP-1.

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Section: Discussionmentioning

confidence: 65%

PPAR-γ Activation Mediates Adipose Depot−Specific Effects on Gene Expression and Lipoprotein Lipase Activity

et al. 2003

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“…Since the in vivo anti-MC effect of progesterone seems to be moderate, we hypothesized that progesterone is metabolized by enzymes of hMR target tissues similar to the way cortisol is metabolized by 11b-HSD-2 to protect the hMR (10,19). We identified a potent and efficient enzyme system in male and in pre-and postmenopausal human kidneys (19,20).…”

Section: Discussionmentioning

confidence: 99%

“…hMR exhibits almost the same affinity for the mineralocorticoid (MC) aldosterone, the glucocorticoid cortisol and the progestogen progesterone (6 -9). In vivo, cortisol is prevented from binding to hMR by the enzyme 11b-hydroxysteroid dehydrogenase type 2 (11b-HSD-2), which converts cortisol to its inactive metabolite cortisone in hMR target cells (10). This enzyme-mediated specificity of hMR was first described by Funder et al (11) and Edwards et al in 1988 (12).…”

Section: Introductionmentioning

confidence: 99%

Agonistic and antagonistic properties of progesterone metabolites at the human mineralocorticoid receptor

Quinkler

Meyer

Bumke-Vogt

et al. 2002

European Journal of Endocrinology

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120

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Objective: Progesterone binds to the human mineralocorticoid receptor (hMR) with nearly the same affinity as do aldosterone and cortisol, but confers only low agonistic activity. It is still unclear how aldosterone can act as a mineralocorticoid in situations with high progesterone concentrations, e.g. pregnancy. One mechanism could be conversion of progesterone to inactive compounds in hMR target tissues. Design: We analyzed the agonist and antagonist activities of 16 progesterone metabolites by their binding characteristics for hMR as well as functional studies assessing transactivation. Methods: We studied binding affinity using hMR expressed in a T7-coupled rabbit reticulocyte lysate system. We used co-transfection of an hMR expression vector together with a luciferase reporter gene in CV-1 cells to investigate agonistic and antagonistic properties. Results: Progesterone and 11b-OH-progesterone (11b-OH-P) showed a slightly higher binding affinity than cortisol, deoxycorticosterone and aldosterone. 20a-dihydro(DH)-P, 5a-DH-P and 17a-OH-P had a 3-to 10-fold lower binding potency. All other progesterone metabolites showed a weak affinity for hMR. 20a-DH-P exhibited the strongest agonistic potency among the metabolites tested, reaching 11.5% of aldosterone transactivation. The agonistic activity of 11b-OH-P, 11a-OH-P and 17a-OH-P was 9, 5.1 and 4.1% respectively. At a concentration of 100 nmol/l, progesterone, 17a-OH-P and 20a-DH-P inhibit nearly 75, 40 and 35% of the transactivation by aldosterone respectively. All other progesterone metabolites tested demonstrate weaker affinity, and agonistic and antagonistic potency. Conclusions: The binding affinity for hMR and the agonistic and antagonistic activity diminish with increasing reduction of the progesterone molecule at C20, C17 and at ring A. We assume that progesterone metabolism to these compounds is a possible protective mechanism for hMR. 17a-OH-P is a strong hMR antagonist and could exacerbate mineralocorticoid deficiency in patients with congenital adrenal hyperplasia.

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“…Further, pregnant mothers threatening preterm birth (~7-10% of all pregnancies), receive antenatal glucocorticoids, to mature the lungs of the fetus prior to birth to reduce neonatal morbidity and mortality [25]. As for cortisol, synthetic glucocorticoids can be catalysed by 11 HSD2, however they are a poor substrate for the enzyme, and more freely cross the placenta than cortisol [33]. The presence of excess maternal glucocorticoids can have positive effects on fetal development and maternal health and in many situations cannot be avoided.…”

Section: Exposure To Synthetic Glucocorticoidsmentioning

confidence: 99%

Sex-Specific Effects of Prenatal Glucocorticoids on Placental Development

Dickinson¹,

O'Connell²,

Walker³

et al. 2012

Glucocorticoids - New Recognition of Our Familiar Friend

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Clinical implications of glucocorticoid metabolism by 11beta-hydroxysteroid dehydrogenases in target tissues

Cited by 47 publications

References 128 publications

PPAR-γ Activation Mediates Adipose Depot−Specific Effects on Gene Expression and Lipoprotein Lipase Activity

PPAR-γ Activation Mediates Adipose Depot−Specific Effects on Gene Expression and Lipoprotein Lipase Activity

Agonistic and antagonistic properties of progesterone metabolites at the human mineralocorticoid receptor

Sex-Specific Effects of Prenatal Glucocorticoids on Placental Development

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