PPARα agonists reduce 11β-hydroxysteroid dehydrogenase type 1 in the liver

11 beta -hydroxysteroid dehydrogenase type 1 (11 beta HSD1) is an enzyme that converts cortisone to the active glucocorticoid, cortisol. Cortisol-cortisone interconversion plays a key role in the regulation of glucose metabolism, since mice deficient in 11 beta HSD1 are resistant to diet-induced hyperglycemia. Peroxisome proliferator activator receptors (PPAR) are key regulators of glucose and Lipid homeostasis. We observed a striking downregulation of murine hepatic 11 beta HSD1 expression and activity after chronic treatment of wild-type mice with PPAR alpha agonists, while 11 beta HSD1 in the livers of PPAR alpha knockout mice, or in mice treat-ed for only 7 h with PPAR alpha agonists, was unaltered. Our results are the first to show PPAR alpha agonists can affect glucocorticoid metabolism in the Liver by altering 11 beta HSD1 expression after chronic treatment. Regulation of active glucocorticoid 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.