11beta-hydroxysteroid dehydrogenase type 1: a tissue-specific regulator of glucocorticoid response.
11beta-hydroxysteroid dehydrogenase type 1 (11beta-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 11beta-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 "11beta-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 11beta-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 11beta-HSD1 activity. Therapeutic inhibition of 11beta-HSD1 reductase activity in patients with obesity and the metabolic syndrome, as well as in glaucoma and osteoporosis, remains an exciting prospect.
Endocrinology, Division of Medical Sciences, University of Birmingham, Queen Elizabeth Hospital, Edgbaston, Birmingham, B15 2TH, UK.
Jeremy W
JW
Tomlinson
Elizabeth A
EA
Walker
Iwona J
IJ
Bujalska
Nicole
N
Draper
Gareth G
GG
Lavery
Mark S
MS
Cooper
Martin
M
Hewison
Paul M
PM
Stewart
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D000595:Amino Acid Sequence; D000818:Animals; D002237:Carbohydrate Dehydrogenases / Q000235:genetics; D003001:Cloning, Molecular; D003349:Cortisone Reductase / Q000172:deficiency / Q000235:genetics; D004791:Enzyme Inhibitors; D015971:Gene Expression Regulation, Enzymologic; D005901:Glaucoma / Q000201:enzymology; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation; D009249:NADP / Q000378:metabolism; D009765:Obesity / Q000201:enzymology; D009928:Organ Specificity; D010024:Osteoporosis / Q000201:enzymology; D011994:Recombinant Proteins; D016415:Sequence Alignment; D013379:Substrate Specificity; D014158:Transcription, Genetic
D004791:Enzyme Inhibitors; D005938:Glucocorticoids; D011994:Recombinant Proteins; D009249:NADP; D002237:Carbohydrate Dehydrogenases; C020552:galactose-6-phosphate dehydrogenase; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D003349:Cortisone Reductase; D006854:Hydrocortisone