Purification and Characterization of the Corticosteroid 1lβ-Dehydrogenase Component of the Rat Liver 1lβ-Hydroxysteroid Dehydrogenase Complex*

Lakshmi, Vijaya M.; Monder, Carl

doi:10.1210/endo-123-5-2390

Cited by 313 publications

(152 citation statements)

References 22 publications

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“…Cell culture media and reagents for reverse transcription of RNA were from Invitrogen (Carlsbad, CA), [1,2,6, H]-cortisol from Amersham Bioscience (Piscataway, NJ), [1,2,6, H]-cortisone from American Radiolabelled Chemicals (St. Louis, MO), the SV total RNA isolation system from Promega (Madison, WI) and reagents for TaqMan realtime PCR from Applied Biosystems (Foster City, CA). Monoclonal antibodies were from Roche Diagnostics (Rotkreuz, Switzerland) and fluorescent antibodies from Molecular Probes (Eugene, OR).…”

Section: Methodsmentioning

confidence: 99%

Hexose‐6‐phosphate dehydrogenase determines the reaction direction of 11β‐hydroxysteroid dehydrogenase type 1 as an oxoreductase

et al. 2004

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The impact of hexose-6-phosphate dehydrogenase (H6PDH) on 11b-hydroxysteroid dehydrogenase (11b-HSD) type 1 activity was investigated upon coexpression in HEK-293 cells. Confocal microscopy analysis indicated colocalisation of both enzymes at the lumenal side of the endoplasmic reticulum (ER) membrane. Functional analysis in intact cells revealed fivefold stimulation of 11b-HSD1 oxoreductase activity and sixfold decrease of dehydrogenase activity upon coexpression with H6PDH, without changing kinetic parameters in cell lysates. Thus, H6PDH directly determines the reaction direction of 11b-HSD1 in intact cells as an oxoreductase without changing intrinsic catalytic properties of 11b-HSD1 by regenerating NADPH in the ER-lumen.

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Section: Methodsmentioning

confidence: 99%

Hexose‐6‐phosphate dehydrogenase determines the reaction direction of 11β‐hydroxysteroid dehydrogenase type 1 as an oxoreductase

et al. 2004

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“…It is now known that there are two isoforms. The type 1 isoform (11βHSD1) first purified from rat liver [33] and then cloned [34] requires pyridine nucleotide cofactor NADP(H) as its cofactor, NADP+ for oxidase which catalyzes the conversion of CORT into 11DHC, or NADPH for reductase to catalyze 11DHC to CORT. It catalyzes both an oxidative and reductive reaction and is referred to as an oxidoreductase.…”

Section: A Rapid Action Of Glucocorticoids Via 11βhsd1mentioning

confidence: 99%

Rapid mechanisms of glucocorticoid signaling in the Leydig cell☆

Lian

Lin

et al. 2008

Steroids

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Stress-mediated elevations in circulating glucocorticoid levels lead to corresponding rapid declines in testosterone production by Leydig cells in the testis. In previous studies we have established that glucocorticoids act on Leydig cells directly, through the classic glucocorticoid receptor (GR), and that access to the GR is controlled prior to the GR by a metabolizing pathway mediated by the type 1 isoform of 11β-hydroxysteroid dehydrogenase (11βHSD1). This enzyme is bidirectional (with both oxidase and reductase activities) and in the rat testis is exclusively localized in Leydig cells where it is abundantly expressed and may catalyze the oxidative inactivation of glucocorticoids. The predominant reductase direction of 11βHSD1 activity in liver cells is determined by an enzyme, hexose-6-phosphate dehydrogenase (H6PDH), on the luminal side of the smooth endoplasmic reticulum (SER). Generation of the pyridine nucleotide cofactor NADPH by H6PDH stimulates the reductase direction of 11βHSD1 resulting in increased levels of active glucocorticoids in liver cells. Unlike liver cells, steroidogenic enzymes including 17β-hydroxysteroid dehydrogenase 3 (17βHSD3) forms the coupling with 11βHSD1. Thus the physiological concentrations of androstenedione serve as a substrate for 17βHSD3 utilizing NADPH to generate NADP+, which drives 11βHSD1 in Leydig cells primarily as an oxidase; thus eliminating the adverse effects of glucocorticoids on testosterone production. At the same time 11βHSD1 generates NADPH which promotes testosterone biosynthesis by stimulating 17βHSD3 in a cooperative cycle. This enzymatic coupling constitutes a rapid mechanism for modulating glucocorticoid control of testosterone biosynthesis. Under stress conditions, glucocorticoids also have rapid actions to suppress cAMP formation thus to lower testosterone production.

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“…At that time, however, 11βHSD had an unexplained two-way function: to convert F into E and, conversely, E into F. Early on, two isoforms of 11βHSD were cloned and characterized: 11βHSD type 1 (11βHSD1) and 11βHSD type 2 (11βHSD2) (3,4). The former is a low-affinity NADP(H)-dependent dehydrogenase/oxoreductase (cortisol to cortisone and vice-versa, respectively), which was originally identified in the liver, but that is also highly expressed in adipose, gonadal, and central nervous system tissues.…”

Section: The Intriguing History Of 11β-hydroxysteroid Dehydrogenasementioning

confidence: 99%

Adipose tissue expression of 11beta-Hydroxysteroid dehydrogenase type 1 in cushing's syndrome and in obesity

Espíndola-Antunes

Kater

2007

Arq Bras Endocrinol Metab

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Glucocorticoids have a major role in determining adipose tissue metabolism and distribution. 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) is a NADPHdependent enzyme highly expressed in the liver and adipose tissue. In most intact cells and tissues it functions as a reductase (to convert inactive cortisone to active cortisol). It has been hypothesized that tissue-specific deregulation of cortisol metabolism may be involved in the complex pathophysiology of the metabolic syndrome (MS) and obesity. Transgenic mice overexpressing 11βHSD1 in adipose tissue develop obesity with all features of the MS, whereas 11βHSD1-knockout mice are protected from both. The bulk of evidences points to an overexpression and increased activity of 11βHSD1 also in human adipose tissue. However, 11βHSD1 seems to adjust local cortisol concentrations independently of its plasma levels. In Cushing's syndrome, 11βHSD1 is downregulated and may not be responsible for the abdominal fat depots; it also undergoes downregulation in response to weight loss in human obesity. The nonselective 11βHSD1 inhibitor carbenoxolone improves insulin sensitivity in humans, and selective inhibitors enhance insulin action in diabetic mice liver, thereby lowering blood glucose. Thus, 11βHSD1 is now emerging as a modulator of energy partitioning and a promising pharmacological target to treat the MS and diabetes. Os glicocorticóides (GC) têm papel importante na determinação do metabolismo e da distribuição do tecido adiposo. A 11β-hidroxisteróide desidrogenase tipo 1 (11βHSD1) é uma enzima dependente de NADPH, altamente expressa nos tecidos hepático e adiposo. Em muitas células e tecidos intactos, ela funciona como redutase (convertendo cortisona em cortisol). Postula-se que uma desregulação tecido-específica do cortisol estaria envolvida na complexa fisiopatologia da síndrome metabólica (SM) e obesidade. Ratos que superexpressam 11βHSD1 no tecido adiposo desenvolvem obesidade e todas as características da SM, enquanto ratos knockout para 11βHSD1 são protegidos. Evidências apontam para uma super-expressão e aumento da atividade 11βHSD1 também no tecido adiposo humano. Entretanto, a 11βHSD1 parece ajustar a concentração local de cortisol independente da sua concentração séri-ca. Na síndrome de Cushing, a expressão da 11βHSD1 é regulada para baixo, não devendo ser a causa dos depósitos de gordura visceral; em obesos, há também regulação para baixo em resposta à perda de peso. A carbenoxolona, um inibidor não seletivo da 11βHSD1, melhora a sensibilidade insulínica em humanos e inibidores seletivos aumentam a sensibilidade insulínica hepática e melhoram o controle glicêmico em ratos diabéticos. Assim, a 11βHSD1 está emergindo como um modulador da compartimentalização de energia e um alvo farmacológico promissor para o tratamento da SM e do diabetes.

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Purification and Characterization of the Corticosteroid 1lβ-Dehydrogenase Component of the Rat Liver 1lβ-Hydroxysteroid Dehydrogenase Complex*

Cited by 313 publications

References 22 publications

Hexose‐6‐phosphate dehydrogenase determines the reaction direction of 11β‐hydroxysteroid dehydrogenase type 1 as an oxoreductase

Hexose‐6‐phosphate dehydrogenase determines the reaction direction of 11β‐hydroxysteroid dehydrogenase type 1 as an oxoreductase

Rapid mechanisms of glucocorticoid signaling in the Leydig cell☆

Adipose tissue expression of 11beta-Hydroxysteroid dehydrogenase type 1 in cushing's syndrome and in obesity

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