PPAR alpha agonists reduce 11 beta-hydroxysteroid dehydrogenase type 1 in the liver

11 beta -hydroxysteroid dehydrogenase type 1 (11 beta HSD1) is an enzyme th at converts cortisone to the active glucocorticoid, cortisol. Cortisol-cort isone interconversion plays a key role in the regulation of glucose metabol ism, since mice deficient in 11 beta HSD1 are resistant to diet-induced hyp erglycemia. Peroxisome proliferator activator receptors (PPAR) are key regu lators of glucose and Lipid homeostasis. We observed a striking downregulat ion of murine hepatic 11 beta HSD1 expression and activity after chronic tr eatment of wild-type mice with PPAR alpha agonists, while 11 beta HSD1 in t he livers of PPAR alpha knockout mice, or in mice treat-ed for only 7 h wit h PPAR alpha agonists, was unaltered. Our results are the first to show PPA R alpha agonists can affect glucocorticoid metabolism in the Liver by alter ing 11 beta HSD1 expression after chronic treatment. Regulation of active g lucocorticoid levels in the liver by PPAR alpha agonists may in turn affect glucose metabolism, consistent with reports of their antidiabetic effects. (C) 2000 Academic Press.