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

Thomas M. Stulnig, Udo Oppermann, Knut R. Steffensen, Gertrud U. Schuster, Jan Åke Gustafsson

Research output: Contribution to journalArticlepeer-review

104 Scopus citations

Abstract

11β-hydroxysteroid dehydrogenase type 1 (11β-HSD-1) converts inactive corticosteroids into biologically active corticosteroids, thereby regulating the local concentration of active glucocorticoids, such as cortisol. 11β-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)-α and -β 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 11β-HSD-1 by ∼50%, paralleled by a significant decline in 11β-HSD-1 enzyme activity. Downregulation of 11β-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 11β-HSD-1 mRNA levels by ∼50% in brown adipose tissue and liver of wild-type but not of LXRα-/-β-/- 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 languageEnglish (US)
Pages (from-to)2426-2433
Number of pages8
JournalDiabetes
Volume51
Issue number8
DOIs
StatePublished - 2002

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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