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Diabetes 51:2426-2433, 2002
© 2002 by the American Diabetes Association, Inc.
Liver X Receptors Downregulate 11ß-Hydroxysteroid Dehydrogenase Type 1 Expression and Activity
1 Department of Medical Nutrition and Biosciences, Karolinska Institutet, Huddinge, Sweden
2 Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD-1) converts inactive corticosteroids into biologically active corticosteroids, thereby regulating the local concentration of active glucocorticoids, such as cortisol. 11ß-HSD-1 is particularly expressed in adipocytes and liver and appears to be causally linked to the development of type 2 diabetes and the metabolic syndrome. Liver X receptor (LXR)-
and -ß are nuclear oxysterol receptors whose key role in lipid metabolic regulation has recently been established. In this study, we show that treatment of adipocytes derived from 3T3-L1 cells and mouse embryonic fibroblasts in vitro with synthetic or natural LXR agonists decreases mRNA expression of 11ß-HSD-1 by 
50%, paralleled by a significant decline in 11ß-HSD-1 enzyme activity. Downregulation of 11ß-HSD-1 mRNA by LXRs started after a lag period of 8 h and required ongoing protein synthesis. Moreover, long-term per os treatment with a synthetic LXR agonist downregulated 11ß-HSD-1 mRNA levels by 50% in brown adipose tissue and liver of wild-type but not of LXR-/-ß-/- mice and was paralleled by downregulation of hepatic PEPCK expression. In conclusion, LXR ligands could mediate beneficial metabolic effects in insulin resistance syndromes including type 2 diabetes by interfering with peripheral glucocorticoid activation.
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