11beta-hydroxysteroid dehydrogenase type 1 as a novel therapeutic target in metabolic and neurodegenerative disease.
11beta-hydroxysteroid dehydrogenase Type 1 (11HSD1) catalyses regeneration of active 11-hydroxy glucocorticoids from inactive 11-keto metabolites within target tissues. Inhibition of 11HSD1 has been proposed as a novel strategy to lower intracellular glucocorticoid concentrations, without affecting circulating glucocorticoid levels and their responsiveness to stress. Increased 11HSD1 activity may be pathogenic, for example, in adipose tissue in obesity. Experiments in transgenic mice and using prototype inhibitors in humans show benefits of 11HSD1 inhibition in liver, adipose and brain tissue in treating features of the metabolic syndrome and cognitive dysfunction with ageing. The clinical development of potent selective 11HSD1 inhibitors is now a high priority.
Walker
Brian R
BR
University of Edinburgh, Endocrinology Unit, Western General Hospital, Edinburgh EH4 2XU, UK. B.Walker@ed.ac.uk
Seckl
Jonathan R
JR
D042842:11-beta-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D003480:Cushing Syndrome / Q000097:blood / Q000188:drug therapy / Q000201:enzymology / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D005938:Glucocorticoids / Q000378:metabolism; D006034:Glycyrrhetinic Acid / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects; D008297:Male; D024821:Metabolic Syndrome / Q000188:drug therapy* / Q000201:enzymology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D019636:Neurodegenerative Diseases / Q000188:drug therapy* / Q000201:enzymology; D009765:Obesity / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D010913:Pituitary-Adrenal System / Q000187:drug effects; D051381:Rats; D011924:Rats, Zucker; D011965:Receptors, Glucocorticoid / Q000378:metabolism
D004791:Enzyme Inhibitors; D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid; D042842:11-beta-Hydroxysteroid Dehydrogenases; D006034:Glycyrrhetinic Acid; D006854:Hydrocortisone