Glucocorticoid-mediated effects on metabolism are reversed by targeting 11 beta hydroxysteroid dehydrogenase type 1 in human skeletal muscle.
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 beta-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 microM cortisone or 0.5 microM 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.


CONCLUSIONS
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.
Salehzadeh
Firoozeh
F
Department of Molecular Medicine and Surgery, Karolinska Institutet, S-171 77 Stockholm, Sweden.
Al-Khalili
Lubna
L
Kulkarni
Sameer S
SS
Wang
Minghan
M
Lönnqvist
Fredrik
F
Krook
Anna
A
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D003348:Cortisone / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D005938:Glucocorticoids / Q000502:physiology*; D005947:Glucose / Q000378:metabolism; D006801:Humans; D006854:Hydrocortisone / Q000494:pharmacology; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000187:drug effects / Q000201:enzymology*; D019308:Palmitic Acid / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology
D005938:Glucocorticoids; D034741:RNA, Small Interfering; D019308:Palmitic Acid; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D005947:Glucose; D003348:Cortisone; D006854:Hydrocortisone