Minireview: 11 beta-hydroxysteroid dehydrogenase type 1 - A tissue-specific amplifier of glucocorticoid action

11 beta -hydroxysteroid dehydrogenases (11 beta -HSDs) catalyze the interco nversion of active glucocorticoids (cortisol, corticosterone) and inert 11- keto forms (cortisone, 11-dehydrocorticosterone). 11 beta -HSD type 2 has a well recognized function as a potent dehydrogenase that rapidly inactivate s glucocorticoids, thus allowing aldosterone selective access to otherwise nonselective mineralocorticoid receptors in the distal nephron. In contrast , the function of 11 beta -HSD type 1 has, until recently, been little unde rstood. 11 beta -HSD1 is an ostensibly reversible oxidoreductase in vitro, which is expressed in liver, adipose tissue, brain, lung, and other glucoco rticoid target tissues. However, increasing data suggest that 11 beta -HSD1 acts as a predominant 11 beta -reductase in many intact cells, whole organ s, and in vivo. This reaction direction locally regenerates active glucocor ticoids within expressing cells, exploiting the substantial circulating lev els of inert 11-keto steroids. While the biochemical determinants of the re action direction are not fully understood, insights to its biological impor tance have been afforded by use of inhibitors in vivo, including in humans, and the generation of knockout mice. Such studies suggest 11 beta -HSD1 ef fectively amplifies glucocorticoid action at least in the liver, adipose ti ssue, and the brain. Inhibition of 11 beta -HSD1 represents a potential tar get for therapy of disorders that might be ameliorated by local reduction o f glucocorticoid action, including type 2 diabetes, obesity, and age-relate d cognitive dysfunction.