Circulating
glucocorticoid (GC) levels are controlled by the Hypothalamo-Pituitary-Adrenal (HPA) axis, but within tissues, GC availability is controlled by the
isoforms of 11β (Beta)-
Hydroxysteroid Dehydrogenase 11β (Beta)-HSD that interconvert inactive
cortisone and active
cortisol. Two
isoforms have been identified; in key metabolic target tissues (including liver and adipose), expression of 11β (Beta)-HSD1 predominates that in vivo converts
cortisone to
cortisol and thus amplifies local GC action. In contrast, in
mineralocorticoid target tissues 11β (Beta)-HSD2 is the
isoform that is most abundantly expressed. This inactivates
cortisol to
cortisone and offers protection for the
mineralocorticoid receptor form occupation and activation by
cortisol. Dysregulated 11β (Beta)-HSD1 activity has been implicated in many
metabolic diseases such as
obesity and diabetes and inhibition of 11β (Beta)-HSD1 represents a promising therapeutic target. Mutations within the gene encoding 11β (Beta)-HSD2 cause the Syndrome of Apparent
Mineralocorticoid Excess and decreases in activity are linked to
hypertension as well as impairment in placental function and neonatal growth. We will discuss the molecular biology and enzymology of 11β (Beta)-HSD and its role in normal physiology and discuss altered 11β (Beta)-HSD activity in pathological states and the potential for therapeutic targeting.