UNIPROT:Q7LGC8 - FACTA Search

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Query: UNIPROT:Q7LGC8 (HSD)
3,196 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The regulation of 11 beta-hydroxysteroid dehydrogenase (11 beta HSD) was studied in cultured human skin fibroblasts. 11-Oxo-reductase activity was 5- to 10-fold higher than 11 beta-dehydrogenase activity. Cells treated with 100 nM dexamethasone (Dex) showed a 3-fold increase in the maximum velocity of both activities without a change in the Km values. Dex induction of 11 beta HSD was half-maximal at 48 h and was blocked by glucocorticoid receptor antagonists. Nonglucocorticoid steroids were ineffective. Removal of serum from the culture medium increased maximum velocity values up to 6-fold. Treatment of cells grown in the absence of serum with 8-bromo-cAMP, phorbol esters, or insulin decreased both 11 beta HSD activities. The effects of Dex treatment and serum removal were additive and were blocked by cycloheximide and actinomycin-D. In all experiments both 11 beta HSD activities were modulated in parallel. Both cortisone (200 nM) and cortisol increased the aromatase activity of fibroblasts in the presence of serum. Prior induction of 11 beta HSD by serum removal increased the potency of cortisone from 10-15% to 50% that of cortisol. We conclude that 1) in human fibroblasts 11 beta HSD appears to be a single protein that is under multifactorial regulation; 2) 11 beta HSD may increase or decrease cortisol availability to glucocorticoid receptors; and 3) plasma cortisone levels may be important in assessing glucocorticoid status.
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PMID:Regulation of 11 beta-hydroxysteroid dehydrogenase activity in human skin fibroblasts: enzymatic modulation of glucocorticoid action. 185 64

To test the hypothesis that insulin mediators serve as the signal transduction system for insulin's steroidogenic actions in human placental cytotrophoblasts, we examined the effects of two inositolglycan insulin mediators, the insulin pH 2.0 chiro-inositol mediator (IM-pH 2.0) and the insulin pH 1.3 myo-inositol mediator (IM-pH 1.3), on cytotrophoblastic steroidogenesis. When human cytotrophoblasts were incubated in medium supplemented with androstenedione for 24 h, treatment with IM-pH 2.0 or IM-pH 1.3 suppressed aromatase activity by 15% (P less than 0.05) and 49% (P less than 0.05), respectively, compared to insulin, which suppressed aromatase activity by 21% (P less than 0.05). When cytotrophoblasts were incubated in medium supplemented with pregnenolone for 24 h, treatment with IM-pH 2.0 or IM-pH 1.3 stimulated 3 beta-hydroxysteroid dehydrogenase (3 beta HSD) activity by 145% (P less than 0.05) and 168% (P less than 0.05), respectively, compared to insulin, which stimulated 3 beta HSD activity by 63% (P less than 0.05). Suppression of aromatase activity and stimulation of 3 beta HSD activity by inositolglycan mediators were both concentration dependent. Moreover, preincubation of cytotrophoblasts with the antiinositolglycan antibody alpha IGP completely abolished insulin's ability to either inhibit aromatase or stimulate 3 beta HSD activity. These results indicate that insulin mediators mimic insulin's effects on cytotrophoblastic aromatase and 3 beta HSD activities and suggest that inositolglycan mediators are the signal transduction mechanism responsible for insulin's regulation of human placental steroid hormone biosynthesis.
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PMID:Insulin mediators are the signal transduction system responsible for insulin's actions on human placental steroidogenesis. 195 80

The placenta is the primary source of estrogens and progesterone during pregnancy. Because pregnant diabetic women are reported to have lower serum estrogen and higher progesterone levels than nondiabetic pregnant women, and placental insulin-like growth factor II (IGF-II) production may be elevated during diabetic pregnancy, the role of IGF-II in the regulation of human cytotrophoblastic aromatase, 3 beta-hydroxysteroid dehydrogenase (3 beta HSD), and P450 cholesterol side-chain cleavage (P450scc) enzyme activities was studied. Incubation of cytotrophoblasts with IGF-II for 24 h significantly diminished the ability of these cells to convert androstenedione to estrogens by 92.3 +/- 6.6 (SE)%. IGF-II could suppress aromatase activity at a concentration as low as 2.0 ng/ml. Preincubation of cells with either insulin, IGF-I, or a monoclonal anti-IGF-I receptor antibody did not alter IGF-II's potent inhibitory effect. Treatment with mannose 6-phosphate alone also resulted in significant suppression of aromatase activity, and concurrent treatment with both mannose 6-phosphate and IGF-II resulted in greater inhibition than with either agent alone. These observations suggest that IGF-II suppresses aromatase activity by activation of its own specific receptor. In contrast, incubation of cytotrophoblasts with IGF-II for 24 h significantly increased the 3 beta HSD activity (as determined by the conversion of pregnenolone to progesterone) and P450scc activity (as determined by the conversion of 25-hydroxycholesterol to progesterone) of these cells. IGF-II's ability to stimulate these enzymatic processes was found to be comparable in magnitude to that of IGF-I. IGF-II-stimulated 3 beta HSD activity was completely inhibited by concurrent treatment with either actinomycin D or cycloheximide, suggesting that new mRNA and protein synthesis are required for IGF-II to exert its stimulatory effect. These studies indicate that IGF-II is a potent inhibitor of human cytotrophoblastic aromatase activity in vitro. In addition, IGF-II can stimulate cytotrophoblastic 3 beta HSD and P450scc activities. Since placental IGF-II production in pregnant diabetic women may be augmented, these observations may help explain the lower serum estrogen and higher progesterone levels associated with pregnancy in the diabetic patient.
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PMID:Insulin-like growth factor II is a potent inhibitor of the aromatase activity of human placental cytotrophoblasts. 222

The placenta is the primary source of progesterone during pregnancy. Because pregnant diabetic women are reported to have higher serum progesterone levels than nondiabetic pregnant women, we studied the roles of insulin and insulin-like growth factor-I (IGF-I) in the regulation of human cytotrophoblastic 3 beta-hydroxysteroid dehydrogenase (3 beta HSD) activity. Incubation of cytotrophoblasts with insulin or IGF-I for 24 h significantly increased the ability of these cells to convert pregnenolone to progesterone by 75.8 +/- 16.5% (+/- SE) and 65.4 +/- 12.7%, respectively. Treatment with either insulin or IGF-I did not alter cytotrophoblastic production of 20 alpha-hydroxypregn-4-en-3-one (the primary metabolite of progesterone), thus demonstrating that these peptides increased progesterone synthesis (i.e. 3 beta HSD activity) rather than decreased progesterone catabolism. Insulin and IGF-I stimulated 3 beta HSD activity at concentrations as low as 50 and 10 ng/ml, respectively. Insulin- and IGF-I-stimulated 3 beta HSD activities were completely inhibited by concurrent treatment with either actinomycin-D or cycloheximide, suggesting that new mRNA and protein synthesis are required for these peptides to exert their effects. Blockade of the IGF-I receptor of cytotrophoblasts with alpha IR-3, a monoclonal anti-IGF-I receptor antibody, prevented the stimulation of 3 beta HSD activity by IGF-I, but did not alter insulin's stimulatory effect. Thus, the two hormones can each stimulate 3 beta HSD activity via activation of their respective receptors. These studies indicate that insulin and IGF-I can regulate human cytotrophoblastic 3 beta HSD activity in vitro. Since pregnant diabetic women manifest peripheral hyperinsulinemia, and IGF-I levels in fetal cord sera from diabetic pregnancies may be elevated, these observations may help explain the elevated serum progesterone levels associated with pregnancy in the diabetic patient.
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PMID:Insulin and insulin-like growth factor-I stimulate the 3 beta-hydroxysteroid dehydrogenase activity of human placental cytotrophoblasts. 255 37

11 beta-Hydroxysteroid dehydrogenase (11 beta HSD) catalyzes the interconversion of cortisol and its inactive metabolite, cortisone, and protects the mineralocorticoid receptor from activation by cortisol. Sodium and fluid retention is a well documented phenomenon in insulin-dependent diabetes mellitus (IDDM), but it is not known whether diabetes-associated alterations in cortisol metabolism contribute to its pathogenesis. Therefore, we evaluated some aspects of cortisol metabolism by measuring urinary metabolites of cortisol and cortisone in eight microalbuminuric and eight normoalbuminuric IDDM patients and eight matched control subjects. In both IDDM groups, the overnight excretion of tetrahydrocortisol (THF), allo-tetrahydrocortisol (allo-THF), and tetrahydrocortisone (THE) was lower than that in the control group (P < 0.05 to P < 0.01). Both the allo-THF/THF ratio, a parameter of 5 alpha/5 beta-reduction of cortisol, and the cortisol to cortisone metabolite ratio (THF+allo-THF/THE), which reflects the overall direction of the cortisol to cortisone interconversion, were lower in the IDDM groups (P < 0.05 to P < 0.01). In the combined subjects (n = 24), allo-THF, allo-THF/THF, and THF+allo-THF/THE were inversely correlated with hemoglobin A1c (r = -0.69, P < 0.001; r = -0.61, P < 0.01; and r = -0.58, P < 0.01, respectively). Upper arm segmental blood volume, estimated by an electrical impedance technique, was positively correlated with the cortisol to cortisone metabolite ratio in both the control subjects (r = 0.77; P < 0.05) and the IDDM patients in whom it was measured (r = 0.56; P < 0.05; n = 13), whereas the regression line was shifted leftward in IDDM (i.e. a lower ratio at the same blood volume; P < 0.03, by analysis of covariance). In seven microalbuminuric IDDM patients, the angiotensin-converting enzyme inhibitor, enalapril (10 mg daily for 6-12 weeks), resulted in a moderate further lowering of the cortisol to cortisone metabolite ratio (P < 0.05). The present data suggest a chronic hyperglycemia-related impairment in the reduction of corticoids to tetrahydro metabolites and an imbalance in 11 beta HSD. Altered 11 beta HSD activity is unlikely to be primarily responsible for the sodium and fluid retention in IDDM. Moreover, an additional mechanism of action of angiotensin-converting enzyme inhibition might be provided by an effect on 11 beta HSD activity.
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PMID:Alterations in cortisol metabolism in insulin-dependent diabetes mellitus: relationship with metabolic control and estimated blood volume and effect of angiotensin-converting enzyme inhibition. 755 88

11 beta-Hydroxysteroid dehydrogenase (11 beta HSD) catalyzes the conversion of corticosterone to inert 11-dehydrocorticosterone, thus regulating glucocorticoid access to intracellular receptors. This type 1 isoform (11 beta HSD-1) is a bidirectional NADPH(H)-dependent enzyme in vitro and is highly expressed in liver, where it is regulated by glucocorticoids, thyroid hormones, estrogen, and GH in vivo. In humans in vivo, enzyme inhibition alters glucose homeostasis, an effect thought to be mediated in the liver. However, detailed investigation of the biology of 11 beta HSD-1 in liver, its function, regulation, and indeed even reaction direction, has been hampered by the lack of clonal hepatic cell lines that express 11 beta HSR-1. Studies of nonhepatic cell lines have suggested that 11 beta HSD-1 is directly regulated by hormones, and transfection of nonhepatic cell lines has sown that reaction direction varies between cell types, possibly reflecting intracellular cosubstrate (NADP+/NADPH) ratios or PH. To investigate reaction direction and gene regulation of 11 beta HSD-1 in hepatocytes, we defined conditions for primary culture of adult rat hepatocytes that maintain high 11 beta HSR-1 messenger RNA expression. In intact primary hepatocytes over a wide range of steroid concentrations (2.5-250 nM), 11 beta-reduction was the predominant reaction direction [33.5 +/- 0.5% conversion of 11-dehydrocorticosterone (25 nM) to corticosterone after 30 min], with undetectable 11 beta-dehydrogenation. However, homogenates of hepatocyte cultures showed plentiful 11 beta-dehydrogenase activity. Treatment of hepatocyte cultures with the metabolic inhibitors sodium azide (5 nM) and KCN (1 nM) altered cellular NADP+/NADPH ratios from 0.244 +/- 0.042 in controls to 0.020 +/- 0.001 and 0.152 +/- 0.009, respectively, but had no effect on 11 beta-reductase or 11 beta- dehydrogenase activity. High concentrations of KCN (10 mM) modestly increased 11 beta-reductase activity (32.4 +/- 1.7% to 48.8 +/- 0.5%, whereas 11 beta-dehydrogenation remained at the limit of detection. Manipulation of culture medium pH (6.2-8.0) had no effect on enzyme activity. Dexamethasone (10-7 M) induced hepatocyte 11 beta-reductase activity from 23.4 +/- 0.7% to only weakly affects reaction direction. Glucocorticoid and insulin regulation of hepatic 11 beta HSD-1 is directly mediated, but other hormonal controls are either lost in culture or mediated indirectly. This primary hepatocyte culture system will allow investigation of the control of 11 beta-reductase activity and its implications for glucocorticoid-regulated hepatic functions.
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PMID:11 beta-hydroxysteroid dehydrogenase is an exclusive 11 beta- reductase in primary cultures of rat hepatocytes: effect of physicochemical and hormonal manipulations. 758 3

Estradiol 17 beta-hydroxysteroid dehydrogenase (17 beta HSD) mediates the interconversion of estrone and estradiol in endocrine-responsive tissues such as the breast. The control of 17 beta HSD expression by all-trans-retinoic acid (RA) in T47D breast cancer cells was examined using a specific 17 beta HSD complementary DNA probe. Two main 17 beta HSD messenger RNA (mRNA) transcripts of 2.2 and 1.3 kilobases (kb) were detected, of which only the 1.3-kb mRNA was regulated. RA increased expression of the 17 beta HSD 1.3-kb mRNA in a dose- and time-dependent manner, and the increased expression of this mRNA by RA was inhibited by a 10-fold excess of a RA antagonist Ro 41-5253. Insulin-like-growth factor-I, interleukin-1, and estradiol, previously shown to increase 17 beta HSD activity in breast cancer cells, had little effect on 17 beta HSD gene expression. To relate the effect of increased 17 beta HSD 1.3-kb mRNA expression to 17 beta HSD activity, the conversion of estrone to estradiol (reductive) and that of estradiol to estrone (oxidative) were measured in intact T47D cell monolayers. Whereas RA increased 17 beta HSD reductive activity, it had no effect on oxidative activity. The addition of excess NAD increased 17 beta HSD oxidative activity in control and RA-treated cells, but the addition of NADH had no effect on 17 beta HSD reductive activity. These results suggest that the increased expression of the 17 beta HSD 1.3-kb mRNA induced by RA is associated with an increase in 17 beta HSD reductive activity, but that endogenous cofactor levels may determine the direction in which this enzyme acts in T47D cells.
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PMID:Regulation of estradiol 17 beta-hydroxysteroid dehydrogenase expression and activity by retinoic acid in T47D breast cancer cells. 801 76

In this report we examined the effects of growth factors and phorbol esters on steroid hydroxylase activity in cultured human thecal and granulosa-lutein cells. Treatment of thecal cells with epidermal growth factor (EGF), fibroblast growth factor (FGF), transforming growth factor-beta (TGF beta), and tetradecanoyl phorbol acetate (TPA) resulted in the inhibition of forskolin- and dibutyryl cAMP-stimulated 17 alpha-hydroxylase activity and 17 alpha-hydroxyprogesterone and dehydroepiandrosterone production. In contrast, cAMP-stimulated 3 beta-hydroxysteroid dehydrogenase (3 beta HSD) activity was enhanced by FGF and TGF beta, and treatment with EGF enhanced cAMP-stimulated progesterone production. cAMP stimulated 3 beta HSD activity was unaffected by TPA (10 nmol/L) treatment, yet TPA inhibited cAMP-stimulated progesterone production. Basal 3 beta HSD activity and progesterone production were inhibited by TPA. In contrast to the inhibitory actions of EGF, FGF, and TGF beta on 17 alpha-hydroxylase expression, insulin and insulin-like growth factor-I enhanced forskolin-stimulated 17 alpha-hydroxylase activity. In granulosa-lutein cells, forskolin-stimulated aromatase activity was suppressed by EGF, FGF, and TPA. TGF beta had no effect on forskolin-stimulated aromatase activity. EGF, FGF, and TGF beta did not affect forskolin-stimulated progesterone production, whereas treatment with TPA inhibited cAMP-stimulated progesterone secretion. These data suggest that growth factors may differentially regulate cAMP-dependent processes in human thecal and granulosa cells of the developing follicle.
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PMID:The effects of growth factors and phorbol esters on steroid biosynthesis in isolated human theca interna and granulosa-lutein cells in long term culture. 802 14

The enzyme 11 beta-hydroxysteroid dehydrogenase (11-HSD) converts corticosterone to the inactive 11-dehydrocorticosterone in the rat. The bioactivity of 11-HSD, expressed as the percentage conversion of 3H-corticosterone to 3H-11-dehydrocorticosterone, was 13.7 +/- 0.4% in rat vascular smooth muscle cells (rVSMC). Cells treated with 100 nM dexamethasone (Dex) showed a 1.4-fold (p < 0.05) increase in 11-HSD activity. Insulin (100 microM) decreased 11-HSD activity by 0.8-fold (p < 0.05). Expression of 11-HSD mRNA was also confirmed in rVSMC by Northern blot analysis. Dexamethasone increased and insulin decreased the levels of 11-HSD mRNA in parallel with the increase in bioactivity. Vascular smooth muscle cells express 11-HSD activity; the access of corticosterone to vascular smooth muscle receptors may be modulated by the enzyme.
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PMID:Expression of 11 beta-hydroxysteroid dehydrogenase mRNA in rat vascular smooth muscle cells. 828 89

We examined the regulation of steroid production in fetal zone cells from midgestation (16-21 weeks) human fetal adrenal glands to elucidate the mechanism by which these cells secrete large quantities of dehydroepiandrosterone sulfate (DHAS) and little cortisol in response to ACTH. Our underlying hypothesis is that estrogen and insulin-like to ACTH. Our underlying hypothesis is that estrogen and insulin-like growth factor-II (IGF-II) modulate the steroidogenic response of fetal zone cells to ACTH, driving steroid production toward DHAS rather than cortisol. We also hypothesize that the effects of IGF-II and estrogen on steroidogenesis are achieved by modulating the expression of key enzymes in the steroidogenic pathway. Basal cortisol secretion by cultured fetal zone cells was below the limit of assay sensitivity (< 0.54 pmol/10(5) cells.24 h), whereas basal DHAS secretion was 210.8 +/- 41.0 pmol/10(5) cells.24 h (mean +/- SE). ACTH-(1-24) increased the secretion of cortisol to 228.96 +/- 6.75 pmol/10(5) cells.24 h and that of DHAS to 2039.8 +/- 121.7 pmol/10(5) cells.24 h. Neither IGF-II nor estradiol (E2) affected basal (no added ACTH) steroid secretion by fetal zone cells. IGF-II increased ACTH-stimulated cortisol and DHAS secretion by fetal zone cells in a dose-dependent fashion. In contrast, E2 at high concentrations (1-10 mumol/L) decreased ACTH-stimulated cortisol production to basal levels, but increased ACTH-stimulated DHAS production 1.5- to 2-fold. Combinations of IGF-II (100 ng/mL) and E2 (1 mumol/L) increased ACTH-stimulated cortisol and DHAS secretion by 1.5- to 2-fold compared with control values. However, compared with cultures exposed to IGF-II alone, inclusion of E2 decreased ACTH-stimulated cortisol secretion by about 60% and increased ACTH-stimulated DHAS secretion by about 50%. IGF-II increased the abundance of ACTH-stimulated mRNAs encoding cholesterol side-chain cleavage cytochrome P450 (P450scc), 17 alpha hydroxylase/17,20 lyase P450 (P450c17), and 3 beta-hydroxysteroid dehydrogenase (3 beta HSD). In addition, IGF-II increased the abundance of mRNA encoding P450c17 under basal conditions, but did not affect the basal expression of P450scc or 3 beta HSD. E2 had no effect on basal expression of these steroidogenic enzymes, but increased the abundance of ACTH-stimulated mRNA encoding P450scc and P450c17. The abundance of mRNA encoding 3 beta HSD was not affected by E2. The effect of IGF-II and E2 in combination on steroidogenic enzyme mRNA abundance was not different from that of IGF-II alone. These data indicate that IGF-II increases ACTH-stimulated steroid production in fetal zone cells by increasing the expression of key steroidogenic enzymes.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Interaction of insulin-like growth factor-II and estradiol directs steroidogenesis in the human fetal adrenal toward dehydroepiandrosterone sulfate production. 839 78

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