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.
Tomlinson
Jeremy W
JW
Endocrinology, Division of Medical Sciences, University of Birmingham, Queen Elizabeth Hospital, Edgbaston, Birmingham, B15 2TH, UK.
Walker
Elizabeth A
EA
Bujalska
Iwona J
IJ
Draper
Nicole
N
Lavery
Gareth G
GG
Cooper
Mark S
MS
Hewison
Martin
M
Stewart
Paul M
PM
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