11β-Hydroxysteroid Dehydrogenase

Stewart, Paul M.; Krozowski, Zygmunt

doi:10.1016/s0083-6729(08)60646-9

Cited by 483 publications

(306 citation statements)

References 349 publications

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“…In addition, it has been shown that DHEA can inhibit 11β-hydroxysteroid dehydrogenase 1 expression in liver and adipose tissues (26). It is proposed that the overexpression of 11β-hydroxysteroid dehydrogenase 1 in adipose tissues increases the local cortisol production and thereby leads to the metabolic syndrome-like status (27,28). In the present study, serum DHEAS was a factor associated with serum ALT, independent of the insulin sensitivity index.…”

Section: Discussionsupporting

confidence: 49%

Serum Dehydroepiandrosterone Sulphate Levels in Patients with Non-Alcoholic Fatty Liver Disease

et al. 2011

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Backgound Dehydroepiandrosterone (DHEA) is an adrenal hormone reported to prevent body weight gain, diabetes mellitus and atherosclerosis. We hypothesized that DHEA is involved in the pathophysiology of nonalcoholic fatty liver disease (NAFLD) often associated with obesity and insulin resistance. In this study, we aimed to examine the clinical significance of serum DHEA sulfate (DHEAS) in patients with NAFLD. Methods We determined serum DHEAS, serum alanine aminotransferase (ALT), serum lipids, plasma fasting glucose and insulin levels in 158 Japanese men who had neither viral hepatic diseases nor alcohol intake exceeding 20 g/day. NAFLD was diagnosed by the presence of fatty change of the liver by echotomographic examination. Results Among the study subjects, 69 were diagnosed as having NAFLD. Their serum DHEAS levels were significantly higher than in 89 subjects without NAFLD. Serum DHEAS levels in 19 NAFLD patients with elevated ALT levels (>40 U/L) were significantly higher than in the other 50 NAFLD patients with normal ALT levels (!40 U/L). Multivariate regression analysis demonstrated that serum ALT was positively correlated with serum DHEAS, serum triglyceride and body mass index. Conclusion Serum DHEAS levels are increased in patients with NAFLD with elevated ALT levels. Increased serum DHEAS may be a component of the pathophysiology of NAFLD.

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Section: Discussionsupporting

confidence: 49%

Serum Dehydroepiandrosterone Sulphate Levels in Patients with Non-Alcoholic Fatty Liver Disease

et al. 2011

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“…In land animals, 11 -HSD-type 2 has a key role in the mineralocorticoid response the kidney (Stewart and Krozowski, 1999). This coincides with the emergence of aldosterone as the main mineralocorticoid in land animals.…”

Section: Recruitment Of Steroidogenic and Steroid-inactivating Enzymementioning

confidence: 73%

Co-evolution of steroidogenic and steroid-inactivating enzymes and adrenal and sex steroid receptors

Baker

2004

Molecular and Cellular Endocrinology

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Abstract. Receptors for the adrenal and sex steroids arose by a series of gene duplications from an ancestral nuclear receptor in a primitive vertebrate, at least 540 million years ago. Sequence analysis indicates many steroidogenic and steroid-inactivating enzymes, including cytochrome P450s and hydroxysteroid dehydrogenases, arose at the same time. The estrogen receptor (ER) appears to be the ancestral steroid receptor. Initially, the redundant duplicated ER had a low specificity for its new ligand. This raises the question: "How was specificity for responses to different steroids regulated early in the evolution of steroid receptors?" Selective expression of these steroid-metabolizing enzymes provided specificity for different steroid responses in primitive vertebrates. 17 -hydroxysteroid dehydrogenase-type 1 (17 -HSD-type 1) and 17 -HSD-type 2, which preferentially catalyze the reduction and oxidation at C17 of androgens and estrogens, respectively, provide an example of this mechanism. Selective expression of either 17 -HSD-type 1 or 17 -HSD-type 2 can regulate synthesis or inactivation of androgens or estrogens in specific cells.Steroids also were important in the evolution of land animals, which began about 400 million years ago.Steroidogenic and steroid-inactivating enzymes were recruited to regulate steroid-mediated responses as organ function became more complex. For example, in the kidney 11 -HSD-type 2 prevents binding of glucocorticoids to the mineralocorticoid receptor, which is crucial for aldosterone-mediated regulation of electrolyte transport in the distal tubule. We propose that 5 steroids, such as dehydroepiandrosterone and its metabolites, were the ligands for the ancestral ER. Understanding the actions of 5 steroids in amphioxus and lamprey may shed light on adrenarche and neurosteroid actions in humans.

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“…Type 2 isoform (11βHSD2), was identified later [35,36], and cloned after purification from the kidney [37,38]. 11βHSD2, having no detectable reductase activity, is known to be an exclusively oxidative enzyme activated by a distinct cofactor, NAD + [39].…”

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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11β-Hydroxysteroid Dehydrogenase

Cited by 483 publications

References 349 publications

Serum Dehydroepiandrosterone Sulphate Levels in Patients with Non-Alcoholic Fatty Liver Disease

Serum Dehydroepiandrosterone Sulphate Levels in Patients with Non-Alcoholic Fatty Liver Disease

Co-evolution of steroidogenic and steroid-inactivating enzymes and adrenal and sex steroid receptors

Rapid mechanisms of glucocorticoid signaling in the Leydig cell☆

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