11β-Hydroxysteroid Dehydrogenase Type 1: A Tissue-Specific Regulator of Glucocorticoid Response

11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) interconverts inactive cortisone and active cortisol. Although bidirectional, in vivo it is believed to function as a reductase generating active glucocorticoid at a prereceptor level, enhancing glucocorticoid receptor activation. In this review, we...

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Published in:Endocrine reviews 2004-10, Vol.25 (5), p.831-866
Main Authors: Tomlinson, Jeremy W, Walker, Elizabeth A, Bujalska, Iwona J, Draper, Nicole, Lavery, Gareth G, Cooper, Mark S, Hewison, Martin, Stewart, Paul M
Format: Article
Language:English
Subjects:
11β-Hydroxysteroid dehydrogenase
Adenine
Adrenals. Interrenals
Adrenocortical hormones. Regulation
Biological and medical sciences
Cortisone
Dehydrogenase
Dehydrogenases
Fundamental and applied biological sciences. Psychology
Glaucoma
Glucocorticoid receptors
Glucocorticoids
Hexose
Hydroxysteroids
Metabolic disorders
Metabolic syndrome
Mutation
NAD
NADPH-diaphorase
Nicotinamide
Osteoporosis
Receptor mechanisms
Reductase
Reductases
Vertebrates: endocrinology
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Summary:11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) interconverts inactive cortisone and active cortisol. Although bidirectional, in vivo it is believed to function as a reductase generating active glucocorticoid at a prereceptor level, enhancing glucocorticoid receptor activation. In this review, we discuss both the genetic and enzymatic characterization of 11β-HSD1, as well as describing its role in physiology and pathology in a tissue-specific manner. The molecular basis of cortisone reductase deficiency, the putative “11β-HSD1 knockout state” in humans, has been defined and is caused by intronic mutations in HSD11B1 that decrease gene transcription together with mutations in hexose-6-phosphate dehydrogenase, an endoluminal enzyme that provides reduced nicotinamide-adenine dinucleotide phosphate as cofactor to 11β-HSD1 to permit reductase activity. We speculate that hexose-6-phosphate dehydrogenase activity and therefore reduced nicotinamide-adenine dinucleotide phosphate supply may be crucial in determining the directionality of 11β-HSD1 activity. Therapeutic inhibition of 11β-HSD1 reductase activity in patients with obesity and the metabolic syndrome, as well as in glaucoma and osteoporosis, remains an exciting prospect.
ISSN:0163-769X
1945-7189
DOI:10.1210/er.2003-0031