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Papers In Press, published online ahead of print October 18, 2005
Pediatrics Dept., University of Alabama at Birmingham, Birmingham, AL 352331711
Corresponding Author: kmccormick{at}peds.uab.edu
11 ß-hydroxysteroid dehydrogenase type 1 (11 ß-HSD1) catylyzes the interconversion of biologically inactive 11 keto derivatives (cortisone, 11-dehydrocorticosterone) to active glucocorticoids (cortisol, corticosterone) in fat, liver and other tissues. It is located in the intraluminal compartment of the endoplasmic reticulum. Inasmuch as an oxo-reductase requires NADPH, we reasoned that 11 ß-HSD1 would be metabolically interconnected with the cytosolic pentose pathway since this pathway is the primary producer of reduced cellular pyridine nucleotides. To test this theory, 11 ß-HSD1 activity and pentose pathway were simultaneously measured in isolated intact rodent adipocytes. Established inhibitors of NAPDH production via the pentose pathway (dehydroandrostenedione or norepinephrine) inhibited 11 ß-HSD1 oxo-reductase while decreasing cellular NADPH content. Conversely these compounds slightly augmented the reverse, or dehydrogenase, reaction of 11 ß-HSD1. Importantly, using isolated intact microsomes, the inhibitors did not directly alter either of the dual microsomal 11 ß-HSD1 and hexose-6-phosphate dehydrogenase system. Metabolites of 11 ß-HSD1 (corticosterone or 11-dehydrocorticosterone) inhibited or increased pentose flux, respectively, demonstrating metabolic interconnectivity. Using isolated intact liver or fat microsomes, glucose-6 phosphate stimulated 11 ß-HSD1 oxo-reductase, and this effect was blocked by selective inhibitors of glucose-6-phosphate transport. In summary, we demonstrate a metabolic interconnection between pentose pathway and 11 ß-HSD1 oxo-reductase activities that is dependent on cytosolic NADPH production. These observations link cytosolic carbohydrate flux with paracrine glucocorticoid formation. The clinical relevance of these findings may be germane to the regulation of paracrine glucocorticoid formation in disturbed nutritional states such as obesity.
J. Biol. Chem, 10.1074/jbc.M506026200
Submitted on June 2, 2005
Revised on September 16, 2005
Accepted on October 18, 2005
Evidence that the 11 beta hydroxysteroid dehydrogenase (11
-HSD1) is regulated be pentose pathway flux: Studies in rat adipocytes and microsomes
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