Faculty Opinions recommendation of Hexose-6-phosphate dehydrogenase confers oxo-reductase activity upon 11 beta-hydroxysteroid dehydrogenase type 1.

2005 ◽  
Author(s):  
Morag Young
Keyword(s):  
Reductase Activity ◽  
Hydroxysteroid Dehydrogenase

scholarly journals Enhancement of Cortisol-Induced 11β-Hydroxysteroid dehydrogenase Type 1 Expression by Interleukin 1β in Cultured Human Chorionic Trophoblast Cells

Endocrinology ◽  
2006 ◽  
Vol 147 (5) ◽  
pp. 2490-2495 ◽  
Author(s):  
Wenjiao Li ◽  
Lu Gao ◽  
Yan Wang ◽  
Tao Duan ◽  
Leslie Myatt ◽  
...  
Keyword(s):  
Gene Expression ◽  
Phospholipase A2 ◽  
Mrna Expression ◽  
Reporter Gene ◽  
Reductase Activity ◽  
Hydroxysteroid Dehydrogenase ◽  
Cytosolic Phospholipase A2 ◽  
Trophoblast Cells ◽  
Cytosolic Phospholipase

Chorion is the most abundant site of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) expression within intrauterine tissues. It is important to study the regulation of 11β-HSD1 expression in the chorion in terms of local cortisol production during pregnancy. Using real-time PCR and enzyme activity assay, we found that cortisol (1 μm) and IL-1β (10 ng/ml) for 24 h significantly increased 11β-HSD1 mRNA expression and reductase activity in cultured human chorionic trophoblasts. A further significant increase of 11β-HSD1 mRNA expression and reductase activity was observed with cotreatment of cortisol and IL-1β. To explore the mechanism of induction, 11β-HSD1 promoter was cloned into pGL3 plasmid expressing a luciferase reporter gene. By transfecting the constructed vector into WISH cells, an amnion-derived cell line, we found that cortisol (1 μm) or IL-1β (10 ng/ml) significantly increased reporter gene expression. Likewise, an additional increase in reporter gene expression was observed with cotreatment of cortisol and IL-β. To explore the physiological significance of 11β-HSD1 induction in the chorion, we studied the effect of cortisol on cytosolic phospholipase A2 and cyclooxygenase 2 expression. We found that treatment of chorionic trophoblast cells with cortisol (1 μm) induced both cytosolic phospholipase A2 and cyclooxygenase 2 mRNA expression. We conclude that cortisol up-regulates 11β-HSD1 expression through induction of promoter activity, and the effect was enhanced by IL-1β, suggesting that more biologically active glucocorticoids could be generated in the fetal membranes in the presence of infection, which may consequently feed forward in up-regulation of prostaglandin synthesis.

scholarly journals Effects of cortisol and oestradiol on hepatic 11beta-hydroxysteroid dehydrogenase type 1 and glucocorticoid receptor proteins in late-gestation sheep fetus

2003 ◽  
Vol 176 (2) ◽  
pp. 175-184 ◽  
Author(s):  
S Gupta ◽  
N Alfaidy ◽  
AC Holloway ◽  
WL Whittle ◽  
SJ Lye ◽  
...  
Keyword(s):  
Glucocorticoid Receptor ◽  
Fetal Liver ◽  
Reductase Activity ◽  
Plasma Concentrations ◽  
Hydroxysteroid Dehydrogenase ◽  
Late Gestation ◽  
Concurrent Administration ◽  
Fetal Plasma ◽  
Fetal Organ

In the late-gestation sheep, increased fetal plasma cortisol concentration and placental oestradiol (E(2)) output contribute to fetal organ maturation, in addition to the onset of parturition. Both cortisol and E(2) are believed to regulate the enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1), which interconverts bioactive 11-hydroxy glucocorticoids and their inactive 11-keto metabolites. 11beta-HSD1, abundantly expressed in fetal liver, operates primarily as a reductase enzyme to produce bioactive cortisol and thus regulates local hepatic glucocorticoid concentrations. Cortisol acts through the glucocorticoid receptor (GR) present in the liver. In this study, we examined the effects of cortisol and E(2) on hepatic 11beta-HSD1 and GR in the liver of chronically catheterized sheep fetuses treated with saline (n=5), cortisol (1.35 mg/h; n=5), saline+4-hydroxyandrostendione, a P450 aromatase inhibitor (4-OHA; 1.44 mg/h; n=5), or cortisol+4-OHA (n=5). Cortisol infusion resulted in increased plasma concentrations of fetal cortisol and E(2); concurrent administration of 4-OHA attenuated the increase in plasma E(2) concentrations. Using immunohistochemistry, we showed that fetal hepatocytes expressed both 11beta-HSD1 and GR proteins. Cortisol treatment increased GR in both cytosol and nuclei of hepatocytes; concurrent administration of 4-OHA was associated with distinct nuclear GR staining. Western blot revealed that cortisol, in the absence of increased E(2) concentrations, significantly increased concentrations of 11beta-HSD1 (34 kDa) and GR (95 kDa) proteins. 11beta-HSD1 enzyme activity was measured in the liver microsomal fraction in the presence of [(3)H]cortisone (10(-)(6) M) or [(3)H]cortisol (10(-)(6) M) and NADPH (reductase activity) or NADP(+) (dehydrogenase activity) respectively. 11beta-HSD1 reductase activity was significantly greater in the presence of cortisol. In summary, we found that, in sheep during late gestation, cortisol increased both 11beta-HSD1 and GR in the fetal liver, and these effects were accentuated in the absence of increased E(2).

scholarly journals Steroid Hormones Related to 11β-hydroxysteroid Dehydrogenase Type 1 in Treated Obesity

2015 ◽  
pp. S121-S133 ◽  
Author(s):  
L. MÁČOVÁ ◽  
L. SOSVOROVÁ ◽  
J. VÍTKŮ ◽  
M. BIČÍKOVÁ ◽  
M. HILL ◽  
...  
Keyword(s):  
Reductase Activity ◽  
Hydroxysteroid Dehydrogenase ◽  
Diet Therapy ◽  
Local Concentration ◽  
Z Score ◽  
Orthogonal Projections ◽  
Projections To Latent Structures ◽  
Latent Structures ◽  
Circulating Levels

The local concentration of glucocorticoids is intensively regulated by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD 1). Human 11β-HSD 1 also reversibly catalyzes the inter-conversion of 7α-hydroxy- and 7β-hydroxy-dehydroepiandrosterone (DHEA) into 7-oxo-DHEA. The cohort of 282 obese adolescents, 154 girls (median age 15.31 years, range 14.17-16.68 years) and 128 boys (median age 14.95 years, range 13.87-16.16 years), BMI (Body Mass Index) >90th percentile was examined. In samples collected before and after one month of reductive diet therapy, circulating levels of steroids were analyzed by liquid chromatography-tandem mass spectrometry and radioimmunoassay methods. The model of the treatment efficacy prediction was calculated. A significant reduction in circulating levels of cortisone, E2 and increased levels of 7β-hydroxy-DHEA after the reductive treatment was observed. Levels of cortisol, DHEA, DHT sustained without any significant change. The predictive Orthogonal Projections to Latent Structures (OPLS) model explained 20.1 % of variability of BMI, z-score change by the basal levels of 7α-hydroxy-DHEA, DHEA, cortisol and E2 as the strongest predictors. Reduced levels of circulating cortisone and reduced ratios of oxygenated/reduced metabolites reflect increased reductase activity of 11β-HSD 1 with reduced BMI, z-score. We hypothesize whether these changes can be attributed to the altered activity of 11β-HSD 1 in the liver.

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 A novel selective 11β-hydroxysteroid dehydrogenase type 1 inhibitor prevents human adipogenesis

2008 ◽  
Vol 197 (2) ◽  
pp. 297-307 ◽  
Author(s):  
I J Bujalska ◽  
L L Gathercole ◽  
J W Tomlinson ◽  
C Darimont ◽  
J Ermolieff ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Mrna Expression ◽  
Adipocyte Differentiation ◽  
Reductase Activity ◽  
Primary Cultures ◽  
Hydroxysteroid Dehydrogenase ◽  
Novel Therapy ◽  
Fatty Acid Binding ◽  
Glucose Output

Glucocorticoid excess increases fat mass, preferentially within omental depots; yet circulating cortisol concentrations are normal in most patients with metabolic syndrome (MS). At a pre-receptor level, 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) activates cortisol from cortisone locally within adipose tissue, and inhibition of 11β-HSD1 in liver and adipose tissue has been proposed as a novel therapy to treat MS by reducing hepatic glucose output and adiposity. Using a transformed human subcutaneous preadipocyte cell line (Chub-S7) and human primary preadipocytes, we have defined the role of glucocorticoids and 11β-HSD1 in regulating adipose tissue differentiation. Human cells were differentiated with 1.0 μM cortisol (F), or cortisone (E) with or without 100 nM of a highly selective 11β-HSD1 inhibitor PF-877423. 11β-HSD1 mRNA expression increased across adipocyte differentiation (P<0.001, n=4), which was paralleled by an increase in 11β-HSD1 oxo-reductase activity (from nil on day 0 to 5.9±1.9 pmol/mg per h on day 16, P<0.01, n=7). Cortisone enhanced adipocyte differentiation; fatty acid-binding protein 4 expression increased 312-fold (P<0.001) and glycerol-3-phosphate dehydrogenase 47-fold (P<0.001) versus controls. This was abolished by co-incubation with PF-877423. In addition, cellular lipid content decreased significantly. These findings were confirmed in the primary cultures of human subcutaneous preadipocytes. The increase in 11β-HSD1 mRNA expression and activity is essential for the induction of human adipogenesis. Blocking adipogenesis with a novel and specific 11β-HSD1 inhibitor may represent a novel approach to treat obesity in patients with MS.

Expression of 11β-hydroxysteroid dehydrogenase type 1 permits regulation of glucocorticoid bioavailability by human dendritic cells

Blood ◽  
2005 ◽  
Vol 106 (6) ◽  
pp. 2042-2049 ◽  
Author(s):  
Lisa Freeman ◽  
Martin Hewison ◽  
Susan V. Hughes ◽  
Katie N. Evans ◽  
Deborah Hardie ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Glucocorticoid Receptors ◽  
Reductase Activity ◽  
Human Monocyte ◽  
Hydroxysteroid Dehydrogenase ◽  
Fine Tuning ◽  
Cd40 Ligation ◽  
And Function ◽  
Human Dendritic Cells

Abstract Glucocorticoids (GCs) exert powerful anti-inflammatory effects that may relate in part to their ability to restrict the differentiation and function of dendritic cells (DCs). Although these inhibitory effects are dependent upon GCs binding to nuclear glucocorticoid receptors (GRs), fine-tuning of GR signaling is achieved by prereceptor interconversion of cortisol that binds GRs with high affinity and cortisone that does not. We show for the first time that human monocyte-derived DCs are able to generate cortisol as a consequence of up-regulated expression of the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). Immature DCs demonstrate selective enhancement of 11β-HSD1 reductase activity, leading to increased conversion of inactive cortisone to active cortisol. Enhancement of GC bioavailability is maintained or increased upon terminal differentiation induced by signals associated with innate immune activation. In marked contrast, maturation induced by CD40 ligation leads to a sharp reduction in cortisol generation by DCs. The differentiation of DCs from monocyte precursors is inhibited at physiologic concentrations of inactive cortisone, an effect that requires activity of the 11β-HSD1 enzyme. In conclusion, prereceptor regulation of endogenous GCs appears to be an important determinant of DC function and represents a potential target for therapeutic manipulation.

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 A Switch in Dehydrogenase to Reductase Activity of 11β-Hydroxysteroid Dehydrogenase Type 1 upon Differentiation of Human Omental Adipose Stromal Cells

2002 ◽  
Vol 87 (3) ◽  
pp. 1205-1210 ◽  
Author(s):  
Iwona J. Bujalska ◽  
Elizabeth A. Walker ◽  
Martin Hewison ◽  
Paul M. Stewart
Keyword(s):  
Dehydrogenase Activity ◽  
Lipoprotein Lipase ◽  
Stromal Cells ◽  
Adipocyte Differentiation ◽  
Reductase Activity ◽  
Hydroxysteroid Dehydrogenase ◽  
Mrna Levels ◽  
Adipose Stromal Cells ◽  
Glycerol 3 Phosphate Dehydrogenase

As exemplified in patients with Cushing’s syndrome, glucocorticoids play an important role in regulating adipose tissue distribution and function, but circulating cortisol concentrations are normal in most patients with obesity. However, human omental adipose stromal cells (ASCs) can generate glucocorticoid locally through the expression of the enzyme 11β-hydroxysteroid dehydrogenase (11β-HSD) type 1 (11β-HSD1), which, in intact cells, has been considered to be an oxoreductase, converting inactive cortisone (E) to cortisol (F). Locally produced F can induce ASC differentiation, but the relationship between 11β-HSD1 expression and adipocyte differentiation is unknown. Primary cultures of paired omental (om) and sc ASC and adipocytes were prepared from 17 patients undergoing elective abdominal surgery and cultured for up to 14 d. Expression and activity of 11β-HSD isozymes were analyzed together with early (lipoprotein lipase) and terminal (glycerol 3 phosphate dehydrogenase) markers of adipocyte differentiation. On d 1 of culture, 11β-HSD1 activity in intact om ASCs exceeded oxoreductase activity in every patient (78.9 ± 24.9 vs. 15.8 ± 3.7 [mean ± se] pmol/mg per hour, P &lt; 0.001), and in sc ASCs, relative activities were similar (40.6 ± 12.2 vs. 36.9 ± 8.8). Conversely, in freshly isolated om adipocytes, reductase activity exceeded dehydrogenase activity (23.6 ± 1.5 vs. 6.2 ± 0.8 pmol/mg per hour, P &lt; 0.01). Following 14 d of culture in serum-free conditions with addition of 10 nm insulin (Ctr) or insulin with 100 nm F (+F), lipoprotein lipase/18S RNA levels increased in both the Ctr- and +F-treated ASCs, but glycerol 3 phosphate dehydrogenase increased only in the +F cultures. In both cases, however, 11β-HSD1 oxoreductase activity exceeded dehydrogenase activity (Ctr: 53.3 ± 9.0 vs. 32.4 ± 10.5, P &lt; 0.05; +F: 65.6 ± 15.6 vs. 37.1 ± 11.5 pmol/mg per hour, P &lt; 0.05), despite no significant changes in 11β-HSD1 mRNA levels. In sc ASCs, dehydrogenase activity was similar to reductase activity in both Ctr- and +F-treated cells. Type 2 11β-HSD expression was undetectable in each case. These data show that in intact, undifferentiated om ASCs, 11β-HSD1 acts primarily as a dehydrogenase, but in mature adipocytes oxoreductase activity predominates. Because glucocorticoids inhibit cell proliferation, we postulate that 11β-HSD1 activity in uncommitted ASCs may facilitate proliferation rather than differentiation. Once early differentiation is initiated, a “switch” to 11β-HSD1 oxoreductase activity generates F, thus promoting adipogenesis. Site-specific regulation of the set-point of 11β-HSD1 activity may be an important mechanism underpinning visceral obesity.

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.

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