title: Human Glucocorticoid Receptor β Regulates Gluconeogenesis and Inflammation in Mouse Liver.
abstract: While in vitro studies have demonstrated that a glucocorticoid receptor (GR) splice isoform, β-isoform of human GR (hGRβ), acts as a dominant-negative inhibitor of the classic hGRα and confers glucocorticoid resistance, the in vivo function of hGRβ is poorly understood. To this end, we created an adeno-associated virus (AAV) to express hGRβ in the mouse liver under the control of the hepatocyte-specific promoter. Genome-wide expression analysis of mouse livers showed that hGRβ significantly increased the expression of numerous genes, many of which are involved in endocrine system disorders and the inflammatory response. Physiologically, hGRβ antagonized GRα's function and attenuated hepatic gluconeogenesis through downregulation of phosphoenolpyruvate carboxykinase (PEPCK) in wild-type (WT) mouse liver. Interestingly, however, hGRβ did not repress PEPCK in GR liver knockout (GRLKO) mice. In contrast, hGRβ regulates the expression of STAT1 in the livers of both WT and GRLKO mice. Chromatin immunoprecipitation (ChIP) and luciferase reporter assays demonstrated that hGRβ binds to the intergenic glucocorticoid response element (GRE) of the STAT1 gene. Furthermore, treatment with RU486 inhibited the upregulation of STAT1 mediated by hGRβ. Finally, our array data demonstrate that hGRβ regulates unique components of liver gene expression in vivo by both GRα-dependent and GRα-independent mechanisms.
authors.affiliation: Signal Transduction Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina, USA.
authors.forename: Bo
authors.initials: B
authors.lastname: He
authors.affiliation: Signal Transduction Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina, USA.
authors.forename: Diana
authors.initials: D
authors.lastname: Cruz-Topete
authors.affiliation: Signal Transduction Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina, USA.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Oakley
authors.affiliation: Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Xiao
authors.initials: X
authors.lastname: Xiao
authors.affiliation: Signal Transduction Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina, USA cidlows1@niehs.nih.gov.
authors.forename: John A
authors.initials: JA
authors.lastname: Cidlowski
mesh_terms: D000818:Animals; D005786:Gene Expression Regulation; D018014:Gene Transfer Techniques; D005943:Gluconeogenesis; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism
chemical_list: D011965:Receptors, Glucocorticoid; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; C411470:glucocorticoid receptor alpha; C121943:glucocorticoid receptor beta