Background/Objectives: The glucocorticoid receptor (GR) is essential for regulating liver energy balance, metabolism, and inflammation. Stress and other factors can impair its function, resulting in glucocorticoid-resistant metabolic liver disease. GR mainly exists in two forms: the glucocorticoid-binding isoform, GRα, and the non-binding isoform, GRβ. The GRβ isoform typically exhibits minimal signaling activity beyond its role as a dominant-negative regulator of GRα, thereby decreasing glucocorticoid responsiveness and potentially causing resistance. Methods: To explore GRβ signaling independent of GRα, we developed mice with adenovirus-induced overexpression of GRβ (GRβ-Ad) and control mice with a vector (Vec-Ad). After five days on a standard diet, these mice received either vehicle or dexamethasone treatment. Liver tissues were collected, and we performed RNA sequencing and advanced PamGene kinome analysis to detect pathway changes in GRβ-Ad mice compared with controls. Results: Significant increases were observed in the expression of genes that inhibit fatty acid oxidation, inflammation, and liver cancer development. There was also a marked difference in serine/threonine kinase activity between GRβ-Ad and control mice. Conclusions: The findings suggest that elevated GRβ levels affect kinase pathways that modulate glucocorticoid signaling, disrupt liver lipid metabolism, and are associated with cancer pathways. Further research is needed to determine whether GRβ functions similarly in humans and to assess its potential contribution to hepatocellular carcinoma (HCC).
Martinez et al. (Tue,) studied this question.