Glucocorticoid-mediated effects on metabolism are reversed by targeting 11 beta hydroxysteroid dehydrogenase type 1 in human skeletal muscle

• Published in: Diabetes/metabolism research and reviews Vol. 25; no. 3; pp. 250 - 258
• Main Authors: Salehzadeh, Firoozeh, Al-Khalili, Lubna, Kulkarni, Sameer S, Wang, Minghan, Lönnqvist, Fredrik, Krook, Anna
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 01.03.2009
• Subjects: 11-beta-Hydroxysteroid Dehydrogenase Type 1 - antagonists & inhibitors; 11-beta-Hydroxysteroid Dehydrogenase Type 1 - metabolism; cell culture; Cell Differentiation - drug effects; Cells, Cultured; Cortisone - pharmacology; Gene Expression - drug effects; glucocorticoids; Glucocorticoids - physiology; Glucose - metabolism; human skeletal muscle; Humans; Hydrocortisone - pharmacology; Medicin och hälsovetenskap; Middle Aged; Muscle, Skeletal - drug effects; Muscle, Skeletal - enzymology; palmitate oxidation; Palmitic Acid - metabolism; pyruvate dehydrogenase kinase 4; RNA, Small Interfering - pharmacology
• ISSN: 1520-7552; 1520-7560; 1520-7560
• DOI: 10.1002/dmrr.944

Background Adipose tissue and liver play important roles in mediating the metabolic actions of glucocorticoids. However, the effects of glucocorticoids on glucose and lipid metabolism in skeletal muscle are not understood completely. Intracellular glucocorticoid action is dependent on 11 β‐hydroxysteroid dehydrogenase 1 (HSD1), an enzyme that converts cortisone to active cortisol. Methods We investigated the direct role of HSD1 in cultured primary human skeletal muscle cells using siRNA and pharmacological inhibitors of the enzyme. Primary human skeletal muscle cells were cultured in the presence of 0.5 µM cortisone or 0.5 µM cortisol for eight days. siRNA was utilized to reduce expression of either HSD1 or pyruvate dehydrogenase kinase (PDK) 4. Effects of pharmacological inhibitors of HSD1 were also studied. Results Exposure to cortisone or cortisol decreased basal glucose uptake and glucose incorporation into glycogen, but was without effect on the insulin‐stimulated response. Glucocorticoid exposure increased palmitate oxidation, as well as the expression of PDK4. siRNA‐mediated reduction or pharmacological inhibition of HSD1 prevented the effects of cortisone, but not cortisol, on metabolic responses. siRNA‐mediated reduction of PDK4 prevented the effect of cortisol to attenuate glycogen synthesis. Conclusion Targeted reduction or pharmacological inhibition of HSD1 in primary human skeletal muscle cells prevents the effects of cortisone, but not cortisol, on glucose metabolism and palmitate oxidation. Furthermore, the glucocorticoid‐mediated reductions in glucose metabolism are dependent on PDK4. Copyright © 2009 John Wiley & Sons, Ltd.