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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.

Original publication

DOI

10.2337/diabetes.51.8.2426

Type

Journal article

Journal

Diabetes

Publication Date

08/2002

Volume

51

Pages

2426 - 2433

Keywords

11-beta-Hydroxysteroid Dehydrogenase Type 1, 3T3 Cells, Adipocytes, Animals, CCAAT-Enhancer-Binding Proteins, Cell Line, DNA Primers, DNA-Binding Proteins, Fibroblasts, Gene Expression Regulation, Enzymologic, Hydroxysteroid Dehydrogenases, Kinetics, Liver X Receptors, Mice, Orphan Nuclear Receptors, RNA, Messenger, Receptors, Cytoplasmic and Nuclear, Receptors, Retinoic Acid, Receptors, Thyroid Hormone, Sterol Regulatory Element Binding Protein 1, Time Factors, Transcription Factors