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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

Addresses

Department of Medical Nutrition and Biosciences, Karolinska Institutet, Huddinge, Sweden. thomas.stulnig@akh-wien.ac.at

Keywords

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