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

Jamieson, Pauline; Walker, BR; Chapman, KE; Andrew, Ruth; Rossiter, Stephen J.; Seckl,

doi:10.1677/joe.0.1650685

Cited by 86 publications

(55 citation statements)

References 35 publications

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“…In vivo, hepatic 11 HSD1 acts primarily as a reductase enzyme, converting inactive cortisone/ deoxycorticosterone to biologically active cortisol/ corticosterone (Penning 1997, Seckl & Chapman 2000. 11 HSD1 and GR have been co-localized in the liver of the rat (Whorwood et al 1992) suggesting that 11 HSD1 may regulate ligand access to GR (Whorwood et al 1992, Jamieson et al 2000, Seckl & Chapman 2000. Glucocorticoids in turn regulate 11 HSD1 expression and activity (Voice et al 1996).…”

Section: Discussionmentioning

confidence: 99%

Repeated maternal glucocorticoid administration and the developing liver in fetal sheep

Sloboda¹,

Newnham²,

Challis³

2002

Journal of Endocrinology

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Prenatal glucocorticoid exposure has been associated with a reduction in birth weight and postnatal alterations in glucose homeostasis and hypothalamic-pituitary-adrenal (HPA) axis function. The mechanisms underlying these responses are unknown, although changes in fetal hepatic development may play an important role. The fetal liver produces key regulators of fuel metabolism and of the developing HPA axis that are altered by glucocorticoids. The local availability of glucocorticoids is regulated, in part, by corticosteroid-binding protein (CBG), glucocorticoid receptors (GR) and by the enzyme 11 -hydroxysteroid dehydrogenase (11 HSD), but the effects of maternal glucocorticoid administration on the expression of these genes in the fetal liver are unknown. 11 HSD1 is the predominant form of this enzyme present in the liver and is responsible for the conversion of cortisone to cortisol. To determine if prenatal glucocorticoid exposure alters fetal hepatic regulation of CBG, 11 HSD1 and GRs, we treated pregnant ewes with betamethasone (0·5 mg/kg) intramuscularly at 104, 111 and 118 days of gestation (term 150 days). Animals were killed at 125 or 146 days of gestation. Maternal betamethasone administration did not alter mean cord plasma glucose but significantly decreased cord plasma insulin levels (P<0·05) at 125 days of gestation. At 146 days of gestation, cord plasma glucose levels were significantly increased without alterations in insulin levels following maternal betamethasone treatment (P<0·05). Maternal betamethasone administration resulted in a significant increase in fetal hepatic 11 HSD1 mRNA and protein levels at 125 days of gestation (P<0·05). CBG mRNA levels were significantly elevated over control at 125 days although levels of CBG protein were not significantly different. GR protein levels were not statistically different at either 125 or 146 days of gestation following glucocorticoid administration. These data suggest that prenatal betamethasone exposure in the ovine fetus results in alterations in cord glucose and insulin levels as well as alterations in hepatic 11 HSD1 mRNA and protein expression. These changes in 11 HSD1 increase the potential to generate local cortisol from circulating cortisone. We speculate that this could affect expression of glucocorticoid-dependent hepatic enzymes involved with the regulation of glucose production and HPA responsiveness.

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Section: Discussionmentioning

confidence: 99%

Repeated maternal glucocorticoid administration and the developing liver in fetal sheep

Sloboda¹,

Newnham²,

Challis³

2002

Journal of Endocrinology

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“…11 -HSD1 resides within the lumen of the endoplasmic reticulum (ER) (Ozols 1995, Odermatt et al 1999 and is bi-directional, being able to catalyze both the dehydrogenase (cortisol to cortisone) and oxo-reductase (cortisone to cortisol) reactions (Agarwal et al 1989). In vivo and in intact cells, oxo-reductase activity predominates (Bujalska et al 1997a, Jamieson et al 2000, Masuzaki et al 2001, but in cellular homogenates or in purified preparations, the enzyme behaves as a dehydrogenase (Lakshmi & Monder 1988); oxo-reductase activity can only be recovered in these situations upon the addition of an artificial NADPH re-generation system, such as can be provided by the activity of glucose-6-phosphate dehydrogenase (G6PD) (Agarwal et al 1990.…”

Section: Introductionmentioning

confidence: 99%

Hexose-6-phosphate dehydrogenase confers oxo-reductase activity upon 11β-hydroxysteroid dehydrogenase type 1

Bujalska¹,

Draper²,

Michailidou³

et al. 2005

Journal of Molecular Endocrinology

149

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Two isozymes of 11 -hydroxysteroid dehydrogenase (11 -HSD) interconvert active cortisol and inactive cortisone. 11 -HSD2 (renal) acts only as a dehydrogenase, converting cortisol to cortisone. 11 -HSD1 (liver) is a bi-directional enzyme in cell homogenates, whereas in intact cells it typically displays oxo-reductase activity, generating cortisol from cortisone. We recently established that cortisone reductase deficiency is a digenic disease requiring mutations in both the gene encoding 11 -HSD1 and in the gene for a novel enzyme located within the lumen of the endoplasmic reticulum (ER), hexose-6-phosphate dehydrogenase (H6PDH). This latter enzyme generates NADPH, the co-factor required for oxo-reductase activity. Therefore, we hypothesized that H6PDH expression may be an important determinant of 11 -HSD1 oxo-reductase activity. Transient transfection of chinese hamster ovary (CHO) cells with 11 -HSD1 resulted in the appearance of both oxo-reductase and dehydrogenase activities in intact cells. Co-transfection of 11 -HSD1 with H6PDH increased oxo-reductase activity whilst virtually eliminating dehydrogenase activity. In contrast, H6PDH had no effect on reaction direction of 11 -HSD2, nor did the cytosolic enzyme, glucose-6-phosphate dehydrogenase (G6PD) affect 11 -HSD1 oxo-reductase activity. Conversely in HEK 293 cells stably transfected with 11 -HSD1 cDNA, transfection of an H6PDH siRNA reduced 11 -HSD1 oxo-reductase activity whilst simultaneously increasing 11 -HSD1 dehydrogenase activity. In human omental preadipocytes obtained from 15 females of variable body mass index (BMI), H6PDH mRNA levels positively correlated with 11 -HSD1 oxo-reductase activity, independent of 11 -HSD1 mRNA levels. H6PDH expression increased 5·3-fold across adipocyte differentiation (P,0·05) and was associated with a switch from 11 -HSD1 dehydrogenase to oxo-reductase activity. In conclusion, H6PDH is a crucial determinant of 11 -HSD1 oxo-reductase activity in intact cells. Through its interaction with 11 -HSD1, H6PDH may represent a novel target in the pathogenesis and treatment of obesity.

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“…11 -HSD1 has a greater affinity for cortisone than cortisol, and generally acts in the reductase direction to produce cortisol from cortisone. Although some dehydrogenase activity has been detected in the fetal liver (Jamieson et al 2000), the net production of bioactive cortisol predominates , Ricketts et al 1998a.…”

Section: Introductionmentioning

confidence: 99%

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

Gupta¹,

Alfaidy²,

Holloway³

et al. 2003

Journal of Endocrinology

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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 11 -hydroxysteroid dehydrogenase type 1 (11 -HSD1), which interconverts bioactive 11-hydroxy glucocorticoids and their inactive 11-keto metabolites. 11 -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 11 -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 11 -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 11 -HSD1 (34 kDa) and GR (95 kDa) proteins. 11 -HSD1 enzyme activity was measured in the liver microsomal fraction in the presence of [ + (dehydrogenase activity) respectively. 11 -HSD1 reductase activity was significantly greater in the presence of cortisol. In summary, we found that, in sheep during late gestation, cortisol increased both 11 -HSD1 and GR in the fetal liver, and these effects were accentuated in the absence of increased E 2 .

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

Cited by 86 publications

References 35 publications

Repeated maternal glucocorticoid administration and the developing liver in fetal sheep

Repeated maternal glucocorticoid administration and the developing liver in fetal sheep

Hexose-6-phosphate dehydrogenase confers oxo-reductase activity upon 11β-hydroxysteroid dehydrogenase type 1

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

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