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

      Diabetes

      11-beta-Hydroxysteroid Dehydrogenase Type 1, 3T3 Cells, Adipocytes, enzymology, physiology, Animals, CCAAT-Enhancer-Binding Proteins, genetics, Cell Line, DNA Primers, DNA-Binding Proteins, metabolism, Fibroblasts, Gene Expression Regulation, Enzymologic, Hydroxysteroid Dehydrogenases, Kinetics, 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

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          Abstract

          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.

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          12145154

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