| First Author | He B | Year | 2015 |
| Journal | Mol Cell Biol | Volume | 36 |
| Issue | 5 | Pages | 714-30 |
| PubMed ID | 26711253 | Mgi Jnum | J:236132 |
| Mgi Id | MGI:5804753 | Doi | 10.1128/MCB.00908-15 |
| Citation | He B, et al. (2015) Human Glucocorticoid Receptor beta Regulates Gluconeogenesis and Inflammation in Mouse Liver. Mol Cell Biol 36(5):714-30 |
| abstractText | While in vitro studies have demonstrated that a glucocorticoid receptor (GR) splice isoform, beta-isoform of human GR (hGRbeta), acts as a dominant-negative inhibitor of the classic hGRalpha and confers glucocorticoid resistance, the in vivo function of hGRbeta is poorly understood. To this end, we created an adeno-associated virus (AAV) to express hGRbeta in the mouse liver under the control of the hepatocyte-specific promoter. Genome-wide expression analysis of mouse livers showed that hGRbeta significantly increased the expression of numerous genes, many of which are involved in endocrine system disorders and the inflammatory response. Physiologically, hGRbeta antagonized GRalpha's function and attenuated hepatic gluconeogenesis through downregulation of phosphoenolpyruvate carboxykinase (PEPCK) in wild-type (WT) mouse liver. Interestingly, however, hGRbeta did not repress PEPCK in GR liver knockout (GRLKO) mice. In contrast, hGRbeta regulates the expression of STAT1 in the livers of both WT and GRLKO mice. Chromatin immunoprecipitation (ChIP) and luciferase reporter assays demonstrated that hGRbeta binds to the intergenic glucocorticoid response element (GRE) of the STAT1 gene. Furthermore, treatment with RU486 inhibited the upregulation of STAT1 mediated by hGRbeta. Finally, our array data demonstrate that hGRbeta regulates unique components of liver gene expression in vivo by both GRalpha-dependent and GRalpha-independent mechanisms. |
