Human Glucocorticoid Receptor β Regulates Gluconeogenesis and Inflammation in Mouse Liver

While in vitro studies have demonstrated that a glucocorticoid receptor (GR) splice isoform, beta-isoform of human GR (hGR beta), acts as a dominant-negative inhibitor of the classic hGR alpha and confers glucocorticoid resistance, the in vivo function of hGR beta is poorly understood. To this end, we created an adeno-associated virus (AAV) to express hGR beta in the mouse liver under the control of the hepatocyte-specific promoter. Genome-wide expression analysis of mouse livers showed that hGR beta significantly increased the expression of numerous genes, many of which are involved in endocrine system disorders and the inflammatory response. Physiologically, hGR beta antagonized GR alpha's function and attenuated hepatic gluconeogenesis through downregulation of phosphoenolpyruvate carboxykinase (PEPCK) in wild-type (WT) mouse liver. Interestingly, however, hGR beta did not repress PEPCK in GR liver knockout (GRLKO) mice. In contrast, hGR beta regulates the expression of STAT1 in the livers of both WT and GRLKO mice. Chromatin immunoprecipitation (ChIP) and luciferase reporter assays demonstrated that hGR beta binds to the intergenic glucocorticoid response element (GRE) of the STAT1 gene. Furthermore, treatment with RU486 inhibited the upregulation of STAT1 mediated by hGR beta. Finally, our array data demonstrate that hGR beta regulates unique components of liver gene expression in vivo by both GR alpha-dependent and GR alpha-independent mechanisms.