scholarly journals Preadipocyte 11β-Hydroxysteroid Dehydrogenase Type 1 Is a Keto-Reductase and Contributes to Diet-Induced Visceral Obesity in Vivo

Endocrinology ◽  
2008 ◽  
Vol 149 (4) ◽  
pp. 1861-1868 ◽  
Author(s):  
R. A. De Sousa Peixoto ◽  
S. Turban ◽  
J. H. Battle ◽  
K. E. Chapman ◽  
J. R. Seckl ◽  
...  
Keyword(s):  
Visceral Fat ◽  
Reductase Activity ◽  
Visceral Obesity ◽  
Hydroxysteroid Dehydrogenase ◽  
Activity Levels ◽  
Preadipocyte Differentiation ◽  
Visceral Fat Accumulation ◽  
Protein Levels

Glucocorticoid excess promotes visceral obesity and cardiovascular disease. Similar features are found in the highly prevalent metabolic syndrome in the absence of high levels of systemic cortisol. Although elevated activity of the glucocorticoid-amplifying enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) within adipocytes might explain this paradox, the potential role of 11β-HSD1 in preadipocytes is less clear; human omental adipose stromal vascular (ASV) cells exhibit 11β-dehydrogenase activity (inactivation of glucocorticoids) probably due to the absence of cofactor provision by hexose-6-phosphate dehydrogenase. To clarify the depot-specific impact of 11β-HSD1, we assessed whether preadipocytes in ASV from mesenteric (as a representative of visceral adipose tissue) and sc tissue displayed 11β-HSD1 activity in mice. 11β-HSD1 was highly expressed in freshly isolated ASV cells, predominantly in preadipocytes. 11β-HSD1 mRNA and protein levels were comparable between ASV and adipocyte fractions in both depots. 11β-HSD1 was an 11β-reductase, thus reactivating glucocorticoids in ASV cells, consistent with hexose-6-phosphate dehydrogenase mRNA expression. Unexpectedly, glucocorticoid reactivation was higher in intact mesenteric ASV cells despite a lower expression of 11β-HSD1 mRNA and protein (homogenate activity) levels than sc ASV cells. This suggests a novel depot-specific control over 11β-HSD1 enzyme activity. In vivo, high-fat diet-induced obesity was accompanied by increased visceral fat preadipocyte differentiation in wild-type but not 11β-HSD1−/− mice. The results suggest that 11β-HSD1 reductase activity is augmented in mouse mesenteric preadipocytes where it promotes preadipocyte differentiation and contributes to visceral fat accumulation in obesity.

scholarly journals Constant expression of hexose-6-phosphate dehydrogenase during differentiation of human adipose-derived mesenchymal stem cells

2008 ◽  
Vol 41 (3) ◽  
pp. 125-133 ◽  
Author(s):  
Silvia Senesi ◽  
Paola Marcolongo ◽  
Ivana Manini ◽  
Rosella Fulceri ◽  
Vincenzo Sorrentino ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Reductase Activity ◽  
Cell Types ◽  
Hydroxysteroid Dehydrogenase ◽  
Endoplasmic Reticulum Membrane ◽  
Adipose Derived Stem Cells ◽  
Protein Levels ◽  
Constant Expression

The reductase activity of 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1) plays an important role in the growth and differentiation of adipose tissue via the prereceptorial activation of glucocorticoids. This enzyme colocalizes with hexose-6-phosphate dehydrogenase (H6PD) at the luminal surface of the endoplasmic reticulum membrane, and the latter enzyme provides NADPH to the former, which can thus act as an 11β-reductase. It was suggested that, during adipogenesis, the increased expression of H6PD causes a dehydrogenase-to-reductase switch in the activity of HSD11B1. However, only the expression of the HSD11B1 has been extensively studied, and little is known about the expression of H6PD. Here, we investigated the expression and the activity of H6PD in the course of the differentiation of human adipose-derived mesenchymal stem cells (ADMSCs) and murine 3T3-L1 cells. It was found that H6PD is already present in adipose-derived stem cells and in 3T3-L1 fibroblasts even before the induction of adipogenesis. Moreover, mRNA and protein levels, as well as the microsomal H6PD activities remained unchanged during the differentiation. At the same time a great induction of HSD11B1 was observed in both cell types. The observed constant expression of H6PD suggests that HSD11B1 acts as a reductase throughout the adipogenesis process in human ADMSCs and murine 3T3-L1 cells.

scholarly journals The Heparin-Binding Domains of IGFBP-2 Mediate Its Inhibitory Effect on Preadipocyte Differentiation and Fat Development in Male Mice

Endocrinology ◽  
2013 ◽  
Vol 154 (11) ◽  
pp. 4146-4157 ◽  
Author(s):  
Gang Xi ◽  
Melissa A. Solum ◽  
Christine Wai ◽  
Laura A. Maile ◽  
Clifford J. Rosen ◽  
...  
Keyword(s):  
Visceral Fat ◽  
Inhibitory Effect ◽  
Heparin Binding ◽  
Preadipocyte Differentiation ◽  
Visceral Fat Accumulation ◽  
Binding Domains ◽  
Triglyceride Content ◽  
Total Fat

IGF-binding protein (IGFBP)-2 overexpression confers resistance to high-fat feeding and inhibits the differentiation of preadipocytes in vitro. However, whether administration of IGFBP-2 can regulate adipogenesis in vivo and the domains that mediate this response have not been defined. IGFBP-2 contains 2 heparin-binding domains (HBD), which are localized in the linker region (HBD1) and C-terminal region (HBD2) of IGFBP-2. To determine the relative importance of these domains, we used synthetic peptides as well as mutagenesis. Both HBD1 and HBD2 peptides inhibited preadipocyte differentiation, but the HBD2 peptide was more effective. Selective substitution of charged residues in the HBD1 or HBD2 regions attenuated the ability of the full-length protein to inhibit cell differentiation, but the HBD2 mutant had the greatest reduction. To determine their activities in vivo, pegylated forms of each peptide were administered to IGFBP-2−/− mice for 12 weeks. Magnetic resonance imaging scanning showed that only the HBD2 peptide significantly reduced (48 ± 9%, P < .05) gain in total fat mass. Both inguinal (32 ± 7%, P < .01) and visceral fat (44 ± 7%, P < .01) were significantly decreased by HBD2 whereas HBD1 reduced only visceral fat accumulation (24 ± 5%, P < .05). The HBD2 peptide was more effective peptide in reducing triglyceride content and serum adiponectin, but only the HBD2 peptide increased serum leptin. These findings demonstrate that the HBD2 domain of IGFBP-2 is the primary region that accounts for its ability to inhibit adipogenesis and that a peptide encompassing this region has activity that is comparable with native IGFBP-2.

scholarly journals 11 beta-hydroxysteroid dehydrogenase type 1 is a predominant 11 beta-reductase in the intact perfused rat liver

2000 ◽  
Vol 165 (3) ◽  
pp. 685-692 ◽  
Author(s):  
PM Jamieson ◽  
BR Walker ◽  
KE Chapman ◽  
R Andrew ◽  
S Rossiter ◽  
...  
Keyword(s):  
Rat Liver ◽  
Reductase Activity ◽  
Chronic Administration ◽  
Selective Inhibition ◽  
Hydroxysteroid Dehydrogenase ◽  
Rat Plasma ◽  
Male Rat ◽  
Perfused Rat Liver

11 beta-Hydroxysteroid dehydrogenase type 1 (11 beta-HSD-1), a regulator of intrahepatocellular glucocorticoid activity, is bidirectional in homogenates but catalyses 11 beta-reduction (regenerating glucocorticoid) in intact primary hepatocytes in culture. To examine this discrepancy at the whole-organ level, we examined 11 beta-HSD-1 activity in the intact bivascularly perfused rat liver. On a single pass through male rat liver, 44+/-5% of 11-dehydrocorticosterone (11-DHC) recovered was 11 beta-reduced to corticosterone, whereas 10+/-1% of corticosterone was 11 beta-dehydrogenated to 11-DHC. 11 beta-Reduction was less in female liver (21+/-2%, P<0.01) and was significantly greater with perfusion of all substrate via the portal vein (50+/-3%) than via the hepatic artery (30+/-2%, P<0.05). 11 beta-Reductase activity was not saturated by 11-DHC (10(-)(9)-10(-)(6) M). Perfusion with carbenoxolone (CBX, 10(-)(6)-10(-)(3 )M) did not alter 11 beta-reduction of 11-DHC. In contrast, pretreatment with CBX in vivo (10 mg/day) for 7 days inhibited 11 beta-reductase (19+/-4% conversion, P<0.01). Concentrations of 11-DHC in male rat plasma were 44+/-6 nM. Thus 11 beta-HSD-1 is predominantly an 11 beta-reductase in the intact rat liver and is only inhibited by chronic administration of CBX. The substantial concentrations of plasma 11-DHC as substrate suggest that 11 beta-HSD-1 activity and its potential selective inhibition could modify glucocorticoid action in vivo.

scholarly journals Down-Regulation of Adipose 11β-Hydroxysteroid Dehydrogenase Type 1 by High-Fat Feeding in Mice: A Potential Adaptive Mechanism Counteracting Metabolic Disease

Endocrinology ◽  
2004 ◽  
Vol 145 (6) ◽  
pp. 2707-2712 ◽  
Author(s):  
Nicholas M. Morton ◽  
Lynne Ramage ◽  
Jonathan R. Seckl
Keyword(s):  
Metabolic Disease ◽  
Metabolic Syndrome ◽  
Visceral Obesity ◽  
Hydroxysteroid Dehydrogenase ◽  
High Fat ◽  
Down Regulation ◽  
Adipose Tissues ◽  
Brown Adipose

Abstract The enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD-1) amplifies intracellular glucocorticoid action in vivo. 11β-HSD-1 activity is increased in adipose tissues of obese humans and genetically obese rodents, providing a mechanistic basis for the similarities between metabolic disease arising from high circulating glucocorticoids (Cushing’s syndrome) and idiopathic obesity/metabolic syndrome where plasma glucocorticoids are typically unaltered. Fat-specific overexpression of 11β-HSD-1 produces a metabolic syndrome in mice, whereas 11β-HSD-1 null mice resist high-fat diet (HF)-induced visceral obesity and its metabolic consequences. Here we compared the effects of chronic (18 wk) HF feeding on adipose 11β-HSD-1 activity in strains of mice that are either resistant (A/J) or prone (C57BL/6J) to metabolic disease. 11β-HSD-1 activity was highest in sc fat, followed by epididymal fat, with lowest activity in the mesenteric visceral depot of both strains. 11β-HSD-1 activity was lower in white adipose tissues of A/J compared with C57BL/6J mice. Chronic HF feeding unexpectedly caused a down-regulation of 11β-HSD-1 in adipose tissues of both strains, despite comparable adiposity. However, A/J mice down-regulated adipose 11β-HSD-1 to a significantly lower level than C57BL/6J mice in white and thermogenic brown adipose tissues. We propose that a lower adipose 11β-HSD-1 set point affords a metabolic protection to A/J mice. Adaptive down-regulation of adipose 11β-HSD-1 in response to chronic HF represents a novel mechanism that may counteract metabolic disease.

scholarly journals Minireview: Hexose-6-Phosphate Dehydrogenase and Redox Control of 11β-Hydroxysteroid Dehydrogenase Type 1 Activity

Endocrinology ◽  
2005 ◽  
Vol 146 (6) ◽  
pp. 2539-2543 ◽  
Author(s):  
Kylie N. Hewitt ◽  
Elizabeth A. Walker ◽  
Paul M. Stewart
Keyword(s):  
Reductase Activity ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Hydroxysteroid Dehydrogenase ◽  
Pentose Phosphate ◽  
Intact Cells ◽  
The Metabolic Syndrome ◽  
Reduced Nicotinamide Adenine Dinucleotide ◽  
Glucose 6 Phosphate Dehydrogenase

Abstract Hexose-6-phosphate dehydrogenase (H6PDH) is a microsomal enzyme that is able to catalyze the first two reactions of an endoluminal pentose phosphate pathway, thereby generating reduced nicotinamide adenine dinucleotide phosphate (NADPH) within the endoplasmic reticulum. It is distinct from the cytosolic enzyme, glucose-6-phosphate dehydrogenase (G6PDH), using a separate pool of NAD(P)+ and capable of oxidizing several phosphorylated hexoses. It has been proposed to be a NADPH regenerating system for steroid hormone and drug metabolism, specifically in determining the set point of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) activity, the enzyme responsible for the activation and inactivation of glucocorticoids. 11β-HSD1 is a bidirectional enzyme, but in intact cells displays predominately oxo-reductase activity, a reaction requiring NADPH and leading to activation of glucocorticoids. However, in cellular homogenates or in purified preparations, 11β-HSD1 is exclusively a dehydrogenase. Because H6PDH and 11β-HSD1 are coexpressed in the inner microsomal compartment of cells, we hypothesized that H6PDH may provide 11β-HSD1 with NADPH, thus promoting oxo-reductase activity in vivo. Recently, several studies have confirmed this functional cooperation, indicating the importance of intracellular redox mechanisms for the prereceptor control of glucocorticoid availability. With the increased interest in 11β-HSD1 oxo-reductase activity in the pathogenesis and treatment of several human diseases including insulin resistance and the metabolic syndrome, H6PDH represents an additional novel candidate for intervention.

scholarly journals Non-invasive in Vivo Assessment of 11β-hydroxysteroid Dehydrogenase type 1 Activity by 19 F-magnetic Resonance Spectroscopy

2021 ◽  
Author(s):  
Gregorio Naredo-Gonzalez ◽  
Rita Upreti ◽  
Maurits A Jansen ◽  
Scott Semple ◽  
Oliver B Sutcliffe ◽  
...  
Keyword(s):  
Magnetic Resonance ◽  
Magnetic Resonance Spectroscopy ◽  
Limit Of Detection ◽  
Reductase Activity ◽  
Fluorine Content ◽  
Hydroxysteroid Dehydrogenase ◽  
Resonance Spectroscopy ◽  
Pharmacodynamic Biomarkers

Abstract 11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) amplifies tissue glucocorticoid levels and is a pharmaceutical target in diabetes and cognitive decline. Clinical translation of inhibitors is hampered by lack of in vivo pharmacodynamic biomarkers. Our goal was to monitor substrates and products of 11β-HSD1 non-invasively in liver via 19 Fluorine magnetic resonance spectroscopy (19 F-MRS). Interconversion of mono/poly-fluorinated substrate/product pairs was studied in Wistar rats (male, n=6) and healthy men (n=3) using 7 T and 3 T MRI scanners, respectively. Here we show that the limit of detection, as absolute fluorine content, was 0.625 μmol in blood. Mono-fluorinated steroids, dexamethasone and 11-dehydrodexamethasone, were detected in phantoms but not in vivo in human liver following oral dosing. A non-steroidal polyfluorinated tracer, 2-(phenylsulfonyl)-1-(4-(trifluoromethyl)phenyl)ethanone and its metabolic product were detected in vivo in rat liver after oral administration of the keto-substrate, giving a readout of reductase activity. Administration of a selective 11β-HSD1 inhibitor in vivo in rats altered total liver 19 F-MRS signal. We conclude that there is insufficient sensitivity to measure mono-fluorinated tracers in vivo in man with current dosage regimens and clinical scanners. However use of a poly-fluorinated tracer allowed detection of hepatic reductase activity in rats and could be developed for translation to man.

scholarly journals Acute In Vivo Regulation of 11β-Hydroxysteroid Dehydrogenase Type 1 Activity by Insulin and Intralipid Infusions in Humans

2006 ◽  
Vol 91 (11) ◽  
pp. 4682-4688 ◽  
Author(s):  
Deborah J. Wake ◽  
Natalie Z. M. Homer ◽  
Ruth Andrew ◽  
Brian R. Walker
Keyword(s):  
Fatty Acids ◽  
Free Fatty Acids ◽  
Reductase Activity ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Hydroxysteroid Dehydrogenase ◽  
Saline Infusion ◽  
Whole Body ◽  
Cortisol Metabolism

Abstract Context: Extraadrenal regeneration of cortisol by 11β-hydroxysteroid dehydrogenase type 1 (11HSD1) is increased after a mixed meal. It is unknown which tissue is responsible and whether this reflects the complex transcriptional control of 11HSD1 or posttranscriptional control exerted by supply of reduced nicotinamide adenine dinucleotide phosphate from hexose-6-phosphate dehydrogenase. Objective: The objective of this study was to test whether hyperinsulinemia and/or increased serum free fatty acids increase whole-body and intraadipose 11HSD1, and whether adipose 11HSD1 switches from dehydrogenase to reductase activity. Methods: In nine healthy men, we measured whole-body cortisol regeneration (by iv infusion of 9,11,12,12-[2H]4-cortisol) and intra-adipose interconversion of cortisol and cortisone (by sc microdialysis infusion of [3H]4-cortisol and [3H]2-cortisone in separate cannulae) during: 1) a hyperinsulinemic euglycemic clamp; 2) iv lipid infusion (Intralipid 20% fat emulsion); and 3) saline infusion, each for 3.5 h. Results: Hyperinsulinemia increased rate of appearance of 9,12,12-[2H]3-cortisol (19.3 ± 0.8 vs. 16.7 ± 1.1 nmol/min with saline, P &lt; 0.001), indicating increased whole-body 11HSD1. Within adipose, the predominant reaction was reductase conversion of cortisone to cortisol (after 3.5 h of saline infusion, reaching 11.0 ± 2.7% per hour reductase vs. 5.2 ± 1.3 dehydrogenase, P &lt; 0.02); insulin increased reductase (reaching 15.8 ± 3.0, P &lt; 0.05) and tended to increase dehydrogenase activity. Intralipid infusion had no effects on whole-body deuterated cortisol metabolism, but increased both dehydrogenase and reductase (reaching 16.7 ± 1.8, P &lt; 0.01) activities in adipose. Conclusions: Hyperinsulinemia and increased free fatty acids induce acute increases in 11HSD1 activity in adipose tissue that are not attributable to a switch from dehydrogenase to reductase. Hyperinsulinemia also increases systemic cortisol regeneration. These effects may enhance intracellular cortisol concentrations after a meal.

scholarly journals 11β-Hydroxysteroid dehydrogenase type 1 inhibition in idiopathic intracranial hypertension: a double-blind randomized controlled trial

2020 ◽  
Vol 2 (1) ◽  
Author(s):  
Keira Markey ◽  
James Mitchell ◽  
Hannah Botfield ◽  
Ryan S Ottridge ◽  
Tim Matthews ◽  
...  
Keyword(s):  
Intracranial Hypertension ◽  
Lumbar Puncture ◽  
Idiopathic Intracranial Hypertension ◽  
Controlled Trial ◽  
Hydroxysteroid Dehydrogenase ◽  
Opening Pressure ◽  
Double Blind ◽  
Randomized Controlled

Abstract Treatment options for idiopathic intracranial hypertension are limited. The enzyme 11β-hydroxysteroid dehydrogenase type 1 has been implicated in regulating cerebrospinal fluid secretion, and its activity is associated with alterations in intracranial pressure in idiopathic intracranial hypertension. We assessed therapeutic efficacy, safety and tolerability and investigated indicators of in vivo efficacy of the 11β-hydroxysteroid dehydrogenase type 1 inhibitor AZD4017 compared with placebo in idiopathic intracranial hypertension. A multicenter, UK, 16-week phase II randomized, double-blind, placebo-controlled trial of 12-week treatment with AZD4017 or placebo was conducted. Women aged 18–55 years with active idiopathic intracranial hypertension (&gt;25 cmH2O lumbar puncture opening pressure and active papilledema) were included. Participants received 400 mg of oral AZD4017 twice daily compared with matching placebo over 12 weeks. The outcome measures were initial efficacy, safety and tolerability. The primary clinical outcome was lumbar puncture opening pressure at 12 weeks analysed by intention-to-treat. Secondary clinical outcomes were symptoms, visual function, papilledema, headache and anthropometric measures. In vivo efficacy was evaluated in the central nervous system and systemically. A total of 31 subjects [mean age 31.2 (SD = 6.9) years and body mass index 39.2 (SD = 12.6) kg/m2] were randomized to AZD4017 (n = 17) or placebo (n = 14). At 12 weeks, lumbar puncture pressure was lower in the AZD4017 group (29.7 cmH2O) compared with placebo (31.3 cmH2O), but the difference between groups was not statistically significant (mean difference: −2.8, 95% confidence interval: −7.1 to 1.5; P = 0.2). An exploratory analysis assessing mean change in lumbar puncture pressure within each group found a significant decrease in the AZD4017 group [mean change: −4.3 cmH2O (SD = 5.7); P = 0.009] but not in the placebo group [mean change: −0.3 cmH2O (SD = 5.9); P = 0.8]. AZD4017 was safe, with no withdrawals related to adverse effects. Nine transient drug-related adverse events were reported. One serious adverse event occurred in the placebo group (deterioration requiring shunt surgery). In vivo biomarkers of 11β-hydroxysteroid dehydrogenase type 1 activity (urinary glucocorticoid metabolites, hepatic prednisolone generation, serum and cerebrospinal fluid cortisol:cortisone ratios) demonstrated significant enzyme inhibition with the reduction in serum cortisol:cortisone ratio correlating significantly with reduction in lumbar puncture pressure (P = 0.005, R = 0.70). This is the first phase II randomized controlled trial in idiopathic intracranial hypertension evaluating a novel therapeutic target. AZD4017 was safe and well tolerated and inhibited 11β-hydroxysteroid dehydrogenase type 1 activity in vivo. Reduction in serum cortisol:cortisone correlated with decreased intracranial pressure. Possible clinical benefits were noted in this small cohort. A longer, larger study would now be of interest.

'Liver-type' 11β-hydroxysteroid dehydrogenase cDNA encodes reductase but not dehydrogenase activity in intact mammalian COS-7 cells

1994 ◽  
Vol 13 (2) ◽  
pp. 167-174 ◽  
Author(s):  
S C Low ◽  
K E Chapman ◽  
C R W Edwards ◽  
J R Seckl
Keyword(s):  
Dehydrogenase Activity ◽  
Rat Liver ◽  
Mammalian Cells ◽  
Reductase Activity ◽  
Hydroxysteroid Dehydrogenase ◽  
Luciferase Reporter ◽  
Luciferase Expression ◽  
Intact Cells ◽  
Mmtv Ltr

ABSTRACT 11β-Hydroxysteroid dehydrogenase (11β-HSD) catalyses the metabolism of corticosterone to inert 11-dehydrocorticosterone, thus preventing glucocorticoid access to otherwise non-selective renal mineralocorticoid receptors (MRs), producing aldosterone selectivity in vivo. At least two isoforms of 11β-HSD exist. One isoform (11β-HSD1) has been purified from rat liver and an encoding cDNA cloned from a rat liver library. Transfection of rat 11β-HSD1 cDNA into amphibian cells with a mineralocorticoid phenotype encodes 11 β-reductase activity (activation of inert 11-dehydrocorticosterone) suggesting that 11β-HSD1 does not have the necessary properties to protect renal MRs from exposure to glucocorticoids. This function is likely to reside in a second 11β-HSD isoform. 11β-HSD1 is co-localized with glucocorticoid receptors (GRs) and may modulate glucocorticoid access to this receptor type. To examine the predominant direction of 11β-HSD1 activity in intact mammalian cells, and the possible role of 11β-HSD in regulating glucocorticoid access to GRs, we transfected rat 11β-HSD1 cDNA into a mammalian kidney-derived cell system (COS-7) which has little endogenous 11β-HSD activity or mRNA expression. Homogenates of COS-7 cells transfected with increasing amounts of 11β-HSD cDNA exhibited a dose-related increase in 11 β-dehydrogenase activity. In contrast, intact cells did not convert corticosterone to 11-dehydrocorticosterone over 24 h, but showed a clear dose-related 11β-reductase activity, apparent within 4 h of addition of 11-dehydrocorticosterone to the medium. To demonstrate that this reflected a change in functional intracellular glucocorticoids, COS-7 cells were co-transfected with an expression vector encoding GR and a glucocorticoid-inducible MMTV-LTR luciferase reporter construct, with or without 11β-HSD. Corticosterone induced MMTV-LTR luciferase expression in the presence or absence of 11β-HSD. 11-Dehydrocorticosterone was without activity in the absence of 11β-HSD, but induced MMTV-LTR luciferase activity in the presence of 11β-HSD. These results indicate that rat 11β-HSD1 can behave exclusively as a reductase in intact mammalian cells. Thus in some tissues in vivo, 11β-HSD1 may regulate ligand access to GRs by reactivating inert glucocorticoids.

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