Physiological roles of 11 beta-hydroxysteroid dehydrogenase type 1 and hexose-6-phosphate dehydrogenase.
OBJECTIVE
Inactive cortisone is converted to active cortisol by the reductase activity of 11 beta-hydroxysteroid dehydrogenase type 1, which can thus increase glucocorticoid effects in target tissues. This paper reviews the functional role(s) of 11 beta-hydroxysteroid dehydrogenase type 1 and examines factors influencing its activity.


RESULTS
In obese humans, 11 beta-hydroxysteroid dehydrogenase type 1 is relatively highly expressed in adipose tissue. In mice, overexpression of 11 beta-hydroxysteroid dehydrogenase type 1 in adipose or liver causes obesity or insulin resistance, respectively, whereas mice lacking 11 beta-hydroxysteroid dehydrogenase type 1 resist diet-induced obesity and are insulin-sensitive. Thus, 11 beta-hydroxysteroid dehydrogenase type 1 is a promising drug target for treating the metabolic syndrome and type 2 diabetes. Studies in vitro and in mutant mice demonstrate that the reductase activity of 11 beta-hydroxysteroid dehydrogenase type 1 depends on reduced nicotinamide adenine dinucleotide phosphate synthesized within the endoplasmic reticulum by hexose-6-phosphate dehydrogenase. Apparent cortisone reductase deficiency is characterized by androgen excess in women or children and decreased urinary excretion of cortisol metabolites. Although polymorphisms in the genes encoding 11 beta-hydroxysteroid dehydrogenase type 1 and hexose-6-phosphate dehydrogenase were initially implicated in this condition, subsequent reports have not confirmed this.


CONCLUSIONS
Hexose-6-phosphate dehydrogenase and 11 beta-hydroxysteroid dehydrogenase type 1 may play important roles in the pathogenesis of obesity and metabolic syndrome. Although the importance of polymorphisms in the corresponding genes remains uncertain, rare mutations have not been ruled out.
White
Perrin C
PC
Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9063, USA. Perrin.white@utsouthwestern.edu
Rogoff
Daniela
D
McMillan
D Randy
DR
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000235:genetics / Q000502:physiology*; D000818:Animals; D002237:Carbohydrate Dehydrogenases / Q000235:genetics / Q000502:physiology*; D003349:Cortisone Reductase / Q000172:deficiency / Q000235:genetics; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005938:Glucocorticoids / Q000378:metabolism; D006801:Humans; D009765:Obesity / Q000503:physiopathology; D011110:Polymorphism, Genetic
D005938:Glucocorticoids; D002237:Carbohydrate Dehydrogenases; C020552:galactose-6-phosphate dehydrogenase; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D003349:Cortisone Reductase