PPARα Agonists Reduce 11β-Hydroxysteroid Dehydrogenase Type 1 in the Liver

11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) 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 11βHSD1 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 11βHSD1 expression and activity after chronic treatment of wild-type mice with PPARα agonists, while 11βHSD1 in the livers of PPARα knockout mice, or in mice treated for only 7 h with PPARα agonists, was unaltered. Our results are the first to show PPARα agonists can affect glucocorticoid metabolism in the liver by altering 11βHSD1 expression after chronic treatment. Regulation of active glucocorticoid levels in the liver by PPARα agonists may in turn affect glucose metabolism, consistent with reports of their antidiabetic effects.