Liver X receptors downregulate 11beta-hydroxysteroid dehydrogenase type 1 expression and activity.

Journal article

11Beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD-1) converts inactive corticosteroids into biologically active corticosteroids, thereby regulating the local concentration of active glucocorticoids, such as cortisol. 11beta-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)-alpha and -beta 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 11beta-HSD-1 by approximately 50%, paralleled by a significant decline in 11beta-HSD-1 enzyme activity. Downregulation of 11beta-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 11beta-HSD-1 mRNA levels by approximately 50% in brown adipose tissue and liver of wild-type but not of LXRalpha(-/-)beta(-/-) 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.

Authors: Stulnig, T; Oppermann, U; Steffensen, K; Schuster, G; Gustafsson, J

• Publication status: Published
• Journal: Diabetes
• Volume: 51
• Issue: 8
• Pages: 2426-2433
• Publication date: 2002-08-01
• DOI: 10.2337/diabetes.51.8.2426
• EISSN: 1939-327X
• ISSN: 0012-1797
• Language: English
• Keywords: RNA, Messenger; Hydroxysteroid Dehydrogenases; Sterol Regulatory Element Binding Protein 1; Cell Line; DNA Primers; Kinetics; Adipocytes; Gene Expression Regulation, Enzymologic; Transcription Factors; DNA-Binding Proteins; Mice; Receptors, Retinoic Acid; 3T3 Cells; Animals; Fibroblasts; Receptors, Thyroid Hormone; Receptors, Cytoplasmic and Nuclear; CCAAT-Enhancer-Binding Proteins; 11-beta-Hydroxysteroid Dehydrogenase Type 1; Time Factors; Orphan Nuclear Receptors