7
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: not found

      Glucocorticoid Regulation of the Promoter of 11β-Hydroxysteroid Dehydrogenase Type 1 Is Indirect and Requires CCAAT/Enhancer-Binding Protein-β

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) converts inert 11keto-glucocorticoids to active 11β-hydroxy forms, thereby amplifying intracellular glucocorticoid action. Up-regulation of 11β-HSD1 in adipose tissue and liver is of pathogenic importance in metabolic syndrome. However, the mechanisms controlling 11β-HSD1 transcription are poorly understood. Glucocorticoids themselves potently increase 11β-HSD1 expression in many cells, providing a potential feed-forward system to pathology. We have investigated the molecular mechanisms by which glucocorticoids regulate transcription of 11β-HSD1, exploiting an A549 cell model system in which endogenous 11β-HSD1 is expressed and is induced by dexamethasone. We show that glucocorticoid induction of 11β-HSD1 is indirect and requires new protein synthesis. A glucocorticoid-responsive region maps to between −196 and −88 with respect to the transcription start site. This region contains two binding sites for CCAAT/enhancer-binding protein (C/EBP) that together are essential for the glucocorticoid response and that bind predominantly C/EBPβ, with C/EBPδ present in a minority of the complexes. Both C/EBPβ and C/EBPδ are rapidly induced by glucocorticoids in A549 cells, but small interfering RNA-mediated knockdown shows that only C/EBPβ reduction attenuates the glucocorticoid induction of 11β-HSD1. Chromatin immunoprecipitation studies demonstrated increased binding of C/EBPβ to the 11β-HSD1 promoter in A549 cells after glucocorticoid treatment. A similar mechanism may apply in adipose tissue in vivo where increased C/EBPβ mRNA levels after glucocorticoid treatment were associated with increased 11β-HSD1 expression. C/EBPβ is a key mediator of metabolic and inflammatory signaling. Positive regulation of 11β-HSD1 by C/EBPβ may link amplification of glucocorticoid action with metabolic and inflammatory pathways and may represent an endogenous innate host-defense mechanism.

          Related collections

          Author and article information

          Journal
          Mol Endocrinol
          Mol. Endocrinol
          mend
          Molecular Endocrinology
          Endocrine Society
          0888-8809
          1944-9917
          September 1, 2008
          : 22
          : 9
          : 2049-2060
          Affiliations
          Endocrinology Unit (S.S., C.L.E., V.K., Z.M., K.A., J.R.S., K.E.C.), Centre for Cardiovascular Sciences, University of Edinburgh, Edinburgh EH16 4TJ, United Kingdom; Department of Pediatrics (S.S., Y.N., T.O.), Hamamatsu University, School of Medicine, Hamamatsu 431-3192, Japan; and Department of Clinical Biochemistry (A.P.C.), Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge CB2 0QQ, United Kingdom
          Author notes
          Address all correspondence and requests for reprints to: Karen E. Chapman, Endocrinology Unit, Centre for Cardiovascular Sciences, Queen’s Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, United Kingdom. E-mail: Karen.Chapman@ 123456ed.ac.uk .
          Article
          PMC5419454 PMC5419454 5419454 4326
          10.1210/me.2007-0489
          5419454
          18617597
          Categories
          Articles
          Custom metadata
          2049
          Article

          Comments

          Comment on this article